Therapeutically active compositions and their methods of use

ABSTRACT

Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.

CLAIM OF PRIORITY

This application claims priority from U.S. Ser. No. 61/584,214, filedJan. 6, 2012 which is incorporated herein by reference in its entirety.

BACKGROUND OF INVENTION

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylationof isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymesbelong to two distinct subclasses, one of which utilizes NAD(+) as theelectron acceptor and the other NADP(+). Five isocitrate dehydrogenaseshave been reported: three NAD(+)-dependent isocitrate dehydrogenases,which localize to the mitochondrial matrix, and two NADP(+)-dependentisocitrate dehydrogenases, one of which is mitochondrial and the otherpredominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also knownas IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded bythis gene is the NADP(+)-dependent isocitrate dehydrogenase found in themitochondria. It plays a role in intermediary metabolism and energyproduction. This protein may tightly associate or interact with thepyruvate dehydrogenase complex. Human IDH2 gene encodes a protein of 452amino acids. The nucleotide and amino acid sequences for IDH2 can befound as GenBank entries NM_002168.2 and NP_002159.2 respectively. Thenucleotide and amino acid sequence for human IDH2 are also described in,e.g., Huh et al., Submitted (November-1992) to the EMBL/GenBank/DDBJdatabases; and The MGC Project Team, Genome Res. 14:2121-2127(2004).

Non-mutant, e.g., wild type, IDH2 catalyzes the oxidativedecarboxylation of isocitrate to α-ketoglutarate (α-KG) thereby reducingNAD⁺ (NADP⁺) to NADH (NADPH), e.g., in the forward reaction:

Isocitrate+NAD⁺(NADP⁺)→α-KG+CO₂+NADH (NADPH)+H⁺.

It has been discovered that mutations of IDH2 present in certain cancercells result in a new ability of the enzyme to catalyze theNAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate(2HG). 2HG is not formed by wild-type IDH2. The production of 2HG isbelieved to contribute to the formation and progression of cancer (Dang,L et al, Nature 2009, 462:739-44).

The inhibition of mutant IDH2 and its neoactivity is therefore apotential therapeutic treatment for cancer. Accordingly, there is anongoing need for inhibitors of IDH2 mutants having alpha hydroxylneoactivity.

SUMMARY OF INVENTION

Described herein are compounds of Structural Formula I, or apharmaceutically acceptable salt or hydrate thereof:

wherein:

-   -   ring A is an optionally substituted 5-6 member monocyclic aryl        or monocyclic heteroaryl;    -   ring B is an optionally substituted 5-6 member monocyclic aryl        or monocyclic heteroaryl;    -   R¹ and R³ are each independently selected from hydrogen, C₁-C₄        alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, and CN, wherein any        alkyl portion of R¹ is optionally substituted with —OH, NH₂,        NH(C₁-C₄ alkyl), or N(C₁-C₄ alkyl)₂;    -   R² is selected from: —(C₁-C₆ alkyl), —(C₂-C₆ alkenyl or        alkynyl), —(C₁-C₆ alkylene)-N(R⁶)—(C₁-C₆ alkylene)-O—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-N(R⁶)—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)(R⁶), —(C₁-C₆ alkylene)-N(R⁶)—S(O)₁₋₂—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-N(R⁶)—S(O)₁₋₂—(C₀-C₆ alkyl)-Q, —(C₁-C₆        alkylene)-S(O)₁₋₂—N(R⁶)(R⁶), —(C₁-C₄        alkylene)-S(O)₁₋₂—N(R⁶)—(C₁-C₆ alkylene)-Q, —C(O)N(R⁶)—(C₁-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkyl),        —C(O)N(R⁶)—(C₁-C₆ alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₀-C₆        alkylene)-Q, —(C₁-C₆ alkylene)-O—C(O)—(C₁-C₆ alkyl), —(C₁-C₆        alkylene)-O—C(O)—(C₀-C₆ alkyl)-Q, —(C₁-C₆ alkylene)-O—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-O—C(O)—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)-O—C(O)—(C₀-C₆        alkylene)-Q, —(C₀-C₆ alkylene)-C(O)N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)N(R⁶)—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)C(O)—(C₁-C₆ alkyl), —(C₁-C₆        alkylene)-N(R⁶)C(O)—(C₀-C₆ alkylene)-Q, —(C₀-C₆        alkylene)-S(O)₀₋₂—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-S(O)₀₋₂—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)—C(O)—N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-Q,        —(C₀-C₆ alkylene)-C(O)—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-Q, wherein:    -   any alkyl or alkylene moiety present in R² is optionally        substituted with one or more —OH, —O(C₁-C₄ alkyl) or halo;    -   any terminal methyl moiety present in R² is optionally replaced        with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;    -   each R⁶ is independently selected from hydrogen and C₁-C₆ alkyl;        and Q is selected from aryl, heteroaryl, carbocyclyl and        heterocyclyl, any of which is optionally substituted; or    -   R¹ and R³ are optionally taken together with the carbon to which        they are attached to form C(═O); or    -   R¹ and R² are optionally taken together to form substituted        carbocyclyl, optionally substituted heterocyclyl or optionally        substituted heteroaryl, wherein:    -   a. when ring A is unsubstituted phenyl, and ring B is phenyl        substituted by methoxy or ethoxy; then said phenyl of ring B is        not further substituted by oxazolyl;    -   b. when ring A is optionally substituted phenyl or optionally        substituted pyridyl, and ring B is optionally substituted        phenyl; then the portion of the compound represented by        —NH—C(R¹)(R²)(R³) is not —NH(CH₂)-aryl;    -   c. when ring A is optionally substituted phenyl, and ring B is        optionally substituted phenyl or pyrrolyl; then the portion of        the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH(CH₂)C(O)NH₂;    -   d. when ring A is phenyl substituted with 2 or more hydroxyl or        methoxy, and ring B is optionally substituted phenyl; then the        portion of the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH-cycloheptyl;    -   e. when ring A is optionally substituted phenyl and ring B is        optionally substituted phenyl; then R¹ and R³ do not form        2,2,6,6,-tetramethylpiperidin-4-yl;    -   f. when ring A and ring B are optionally substituted phenyl;        then the portion of the compound represented by        —NH—C(R¹)(R²)(R³) is not cysteine, optionally substituted        phenylalanine or leucine or methyl ester thereof;    -   g. when ring A is phenyl or pyridin-3-yl optionally substituted        with one or more substituents selected from halo, methyl or CF₃,        and ring B is phenyl optionally substituted with one or more        substituents selected from halo, methyl, CF₃, methoxy,        CH═C(phenyl)CN; then the portion of the compound represented by        —NHC(R¹)(R²)(R³) is other than —NH(C₁-C₈        alkylene)-N(R^(a))(R^(a)), —NH-1-(aminomethyl)cyclopentylmethyl,        —NH-4-(aminomethyl)cyclohexylmethyl, wherein each R^(a) is        hydrogen, C₁-C₄ alkyl or two R^(a)s are taken together with the        nitrogen to which they are commonly bound to form morpholin-4-yl        or pipieridin-1-yl;    -   h. when ring A is phenyl, 4-chlorophenyl or 4-methyl phenyl and        ring B is 4-chlorophenyl or 3,4-dichlorophenyl; then the portion        of the compound represented by —NHC(R¹)(R²)(R³) is not        —NH-isopropyl;    -   i. when ring A is unsubstituted phenyl and the portion of the        compound represented by —NHC(R¹)(R²)(R³) is —NH—CH₂CH₂N(CH₃)₂,        —NH—CH₂CH₂-morpholin-4-yl or —NH—CH₂CH₂OH; then ring B is other        than oxadiazole, imidazole, thiazole or oxazole each of which is        substituted with —C(O)NHR^(b), wherein R^(b) is isopropyl,        cyclopropyl or 2-chloro-6-methylphenyl;    -   j. when ring A is phenyl substituted with SO₂OH or SO₂Na and        ring B is phenyl, or when ring B is phenyl substituted with        SO₂OH and ring A is substituted phenyl; then the portion of the        compound represented by —NHC(R¹)(R²)(R³) is not —NH(CH₂)₂OH or        —NH(CH₂)CH(OH)CH₃; and    -   k. the compound is other than:

-   (E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacrylonitrile,

-   4-((4-((furan-2-ylmethyl)amino)-6-(pyridin-4-yl)-1,3,5-triazin-2-yl)amino)phenol,    3-(4-((5-aminopentyl)amino)-6-((3-fluorophenyl)amino)-1,3,5-triazin-2-yl)phenol,

-   N²,6-bis(3-fluorophenyl)-N⁴-(piperidin-3-yl)-1,3,5-triazine-2,4-diamine,

-   N²-butyl-6-phenyl-N⁴-(p-tolyl)-1,3,5-triazine-2,4-diamine,    N²-cyclohexyl-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine,

-   (R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-yl)amino)-4-methylbenzamide,

-   2-chloro-4-(methylsulfonyl)-N-[4-(phenylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,

-   N²-(2-methoxyethyl)-N⁴-phenyl-6-[5-[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine,

-   N²-(2-furanylmethyl)-6-phenyl-N⁴-[3-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine,

-   6-(3-methoxyphenyl)-N²-methyl-N⁴-(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,

-   N²-butyl-N⁴-(4-methylphenyl)-6-phenyl-1,3,5-triazine-2,4-diamine,    and

-   4-[[4-(5-chloro-2-methylphenyl)-6-(methylamino)]-1,3,5-triazin-2-yl]amino-benzenemethanol.

The compound of Formula I or II or as described in any one of theembodiments herein inhibits mutant IDH2, particularly mutant IDH2 havingalpha hydroxyl neoactivity. Also described herein are pharmaceuticalcompositions comprising a compound of Formula I and methods of usingsuch compositions to treat cancers characterized by the presence of amutant IDH2.

DETAILED DESCRIPTION

The details of construction and the arrangement of components set forthin the following description or illustrated in the drawings are notmeant to be limiting. Other embodiments and different ways to practicethe invention are expressly included. Also, the phraseology andterminology used herein is for the purpose of description and should notbe regarded as limiting. The use of “including,” “comprising,” or“having,” “containing”, “involving”, and variations thereof herein, ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items.

DEFINITIONS

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a fully saturated or unsaturated hydrocarbonchain that may be a straight chain or branched chain, containing theindicated number of carbon atoms. For example, C₁-C₁₂ alkyl indicatesthat the group may have from 1 to 12 (inclusive) carbon atoms in it. Theterm “haloalkyl” refers to an alkyl in which one or more hydrogen atomsare replaced by halo, and includes alkyl moieties in which all hydrogenshave been replaced by halo (e.g., perfluoroalkyl). The terms “arylalkyl”or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom isreplaced by an aryl group. Aralkyl includes groups in which more thanone hydrogen atom has been replaced by an aryl group. Examples of“arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl,9-fluorenyl, benzhydryl, and trityl groups. The term “alkyl” includes“alkenyl” and “alkynyl”.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH₂CH(CH₃)CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and characterized in having one or moretriple bonds. Examples of alkynyl groups include, but are not limitedto, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbonsmay optionally be the point of attachment of the alkynyl substituent.

The term “alkoxy” refers to an —O-alkyl radical. The term “haloalkoxy”refers to an alkoxy in which one or more hydrogen atoms are replaced byhalo, and includes alkoxy moieties in which all hydrogens have beenreplaced by halo (e.g., perfluoroalkoxy).

Unless otherwise specified, the term “aryl” refers to a fully aromaticmonocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples ofaryl moieties are phenyl, naphthyl, and anthracenyl. Unless otherwisespecified, any ring atom in an aryl can be substituted by one or moresubstituents. The term “monocyclic aryl” means a monocyclic fullyromatic hydrocarbon ring system, optionally substituted by one or moresubstituents which can not form a fused bicyclic or tricyclic ring.

The term “carbocyclyl” refers to a non-aromatic, monocyclic, bicyclic,or tricyclic hydrocarbon ring system. Carbocyclyl groups include fullysaturated ring systems (e.g., cycloalkyls), and partially saturated ringsystems.

The term “cycloalkyl” as employed herein includes saturated cyclic,bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12carbons. Any ring atom can be substituted (e.g., by one or moresubstituents). Examples of cycloalkyl moieties include, but are notlimited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, andnorbornyl.

Unless otherwise specified, the term “heteroaryl” refers to a fullyaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (or the oxidized forms such asN⁺—O⁻, S(O) and S(O)₂). The term “monocyclic heteroaryl” means amonocyclic fully romatic ring system having 1-3 heteroatoms, optionallysubstituted by one or more substituents which can not form a fusedbicyclic or tricyclic ring.

The term “heterocyclyl” refers to a nonaromatic, 3-10 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (or the oxidized forms such as N⁺—O⁻, S(O) and S(O)₂).The heteroatom may optionally be the point of attachment of theheterocyclyl substituent. Examples of heterocyclyl include, but are notlimited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclylgroups include fully saturated ring systems, and partially saturatedring systems.

Bicyclic and tricyclic ring systems containing one or more heteroatomsand both aromatic and non-aromatic rings are considered to beheterocyclyl or heteroaryl groups. Bicyclic or tricyclic ring systemswhere an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyland the point of attachment from the ring system to the rest of themolecule is through an aromatic ring are considered to be aryl orheteroaryl groups, respectively. Bicyclic or tricyclic ring systemswhere an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyland the point of attachment from the ring system to the rest of themolecule is through the non-aromatic ring are considered to becarbocyclyl (e.g., cycloalkyl) or heterocyclyl groups, respectively.

Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclylgroups, either alone or a part of a group (e.g., the aryl portion of anaralkyl group), are optionally substituted at one or more substitutableatoms with, unless specified otherwise, substituents independentlyselected from: halo, —C≡N, C₁-C₄ alkyl, ═O, —OR^(b), —OR^(b′), —SR^(b),—SR^(b′), —(C₁-C₄ alkyl)-N(R^(b))(R^(b)), —(C₁-C₄alkyl)-N(R^(b))(R^(b′)), —N(R^(b))(R^(b)), —N(R^(b))(R^(b′)), —O—(C₁-C₄alkyl)-N(R^(b))(R^(b)), —O—(C₁-C₄ alkyl)-N(R^(b))(R^(b′)), —(C₁-C₄alkyl)-O—(C₁-C₄ alkyl)-N(R^(b))(R^(b)), —(C₁-C₄ alkyl)-O—(C₁-C₄alkyl)-N(R^(b))(R^(b′)), —C(O)—N(R^(b))(R^(b)), —(C₁-C₄alkyl)-C(O)—N(R^(b))(R^(b)), —(C₁-C₄ alkyl)-C(O)—N(R^(b))(R^(b)),—OR^(b′), R^(b′), —C(O)(C₁-C₄ alkyl), —C(O)R^(b′),—C(O)N(R^(b′))(R^(b)), —N(R^(b))C(O)(R^(b)), —N(R^(b))C(O)(R^(b)),—N(R^(b))SO₂(R^(b)), —SO₂N(R^(b))(R^(b)), —N(R^(b))SO₂(R^(b)), and—SO₂N(R^(b))(R^(b′)), wherein any alkyl substituent is optionallyfurther substituted with one or more of —OH, —O—(C₁-C₄ alkyl), halo,—NH₂, —NH(C₁-C₄ alkyl), or —N(C₁-C₄ alkyl)₂;

-   -   each R^(b) is independently selected from hydrogen, and —C₁-C₄        alkyl; or    -   two R^(b)s are taken together with the nitrogen atom to which        they are bound to form a 4- to 8-membered heterocyclyl        optionally comprising one additional heteroatom selected from N,        S, and O; and    -   each R^(b′) is independently selected from C₃-C₇ carbocyclyl,        phenyl, heteroaryl, and heterocyclyl, wherein one or more        substitutable positions on said phenyl, cycloalkyl, heteroaryl        or heterocycle substituent is optionally further substituted        with one or more of —(C₁-C₄ alkyl), —(C₁-C₄ fluoroalkyl), —OH,        —O—(C₁-C₄ alkyl), —O—(C₁-C₄ fluoroalkyl), halo, —NH₂, —NH(C₁-C₄        alkyl), or —N(C₁-C₄ alkyl)₂.

Heterocyclyl groups, either alone or as part of a group, are optionallysubstituted on one or more any substitutable nitrogen atom with oxo,—C₁-C₄ alkyl, or fluoro-substituted C₁-C₄ alkyl.

The term “substituted” refers to the replacement of a hydrogen atom byanother group.

As used herein, the term “elevated levels of 2HG” means 10%, 20% 30%,50%, 75%, 100%, 200%, 500% or more 2HG then is present in a subject thatdoes not carry a mutant IDH2 allele. The term “elevated levels of 2HG”may refer to the amount of 2HG within a cell, within a tumor, within anorgan comprising a tumor, or within a bodily fluid.

The term “bodily fluid” includes one or more of amniotic fluidsurrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum,Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate,interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage orphlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears,urine, vaginal secretion, or vomit.

As used herein, the terms “inhibit” or “prevent” include both completeand partial inhibition and prevention. An inhibitor may completely orpartially inhibit the intended target.

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease/disorder (e.g.,a cancer), lessen the severity of the disease/disorder (e.g., a cancer)or improve the symptoms associated with the disease/disorder (e.g., acancer).

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patient(referred to as a patient) having a disorder, e.g., a disorder describedherein or a normal subject. The term “non-human animals” of one aspectof the invention includes all vertebrates, e.g., non-mammals (such aschickens, amphibians, reptiles) and mammals, such as non-human primates,domesticated and/or agriculturally useful animals, e.g., sheep, dog,cat, cow, pig, etc.

Compounds

Provided is a compound of Structural Formula I, or a pharmaceuticallyacceptable salt or hydrate thereof:

wherein:

ring A is an optionally substituted 5-6 member monocyclic aryl ormonocyclic heteroaryl;

ring B is an optionally substituted 5-6 member monocyclic aryl ormonocyclic heteroaryl;

R¹ and R³ are each independently selected from hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, and CN, wherein any alkyl portion of R¹is optionally substituted with —OH, NH₂, NH(C₁-C₄ alkyl), or N(C₁-C₄alkyl)₂;

R² is selected from: —(C₁-C₆ alkyl), —(C₂-C₆ alkenyl or alkynyl),—(C₁-C₆ alkylene)-N(R⁶)—(C₁-C₆ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₆alkylene)-N(R⁶)—(C₀-C₆ alkylene)-Q, —(C₁-C₆ alkylene)-N(R⁶)(R⁶), —(C₁-C₆alkylene)-N(R⁶)—S(O)₁₋₂—(C₁-C₆ alkyl), —(C₁-C₆alkylene)-N(R⁶)—S(O)₁₋₂—(C₀-C₆ alkyl)-Q, —(C₁-C₆alkylene)-S(O)₁₋₂—N(R⁶)(R⁶), —(C₁-C₄ alkylene)-S(O)₁₋₂—N(R⁶)—(C₁-C₆alkylene)-Q, —C(O)N(R⁶)—(C₁-C₆ alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆alkyl), —C(O)N(R⁶)—(C₁-C₆ alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₀-C₆alkylene)-Q, —(C₁-C₆ alkylene)-O—C(O)—(C₁-C₆ alkyl), —(C₁-C₆alkylene)-O—C(O)—(C₀-C₆ alkyl)-Q, —(C₁-C₆ alkylene)-O—(C₁-C₆ alkyl),—(C₁-C₆ alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₀-C₆ alkylene)-C(O)—(C₀-C₆alkylene)-O—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-C(O)—(C₀-C₆alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₁-C₆ alkylene)-O—C(O)—(C₁-C₆ alkyl),—(C₁-C₆ alkylene)-O—C(O)—(C₀-C₆ alkylene)-Q, —(C₀-C₆alkylene)-C(O)N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-C(O)N(R⁶)—(C₀-C₆alkylene)-Q, —(C₁-C₆ alkylene)-N(R⁶)C(O)—(C₁-C₆ alkyl), —(C₁-C₆alkylene)-N(R⁶)C(O)—(C₀-C₆ alkylene)-Q, —(C₀-C₆ alkylene)-S(O)₀₋₂—(C₁-C₆alkyl), —(C₀-C₆ alkylene)-S(O)₀₋₂—(C₀-C₆ alkylene)-Q, —(C₁-C₆alkylene)-N(R⁶)—C(O)—N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-Q, —(C₀-C₆alkylene)-C(O)—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-C(O)—(C₀-C₆ alkylene)-Q,wherein:

any alkyl or alkylene moiety present in R² is optionally substitutedwith one or more —OH, —O(C₁-C₄ alkyl) or halo;

any terminal methyl moiety present in R² is optionally replaced with—CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

each R⁶ is independently selected from hydrogen and C₁-C₆ alkyl; and

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Qis optionally substituted; or

-   -   R¹ and R³ are optionally taken together with the carbon to which        they are attached to form C(═O); or    -   R¹ and R² are optionally taken together to form an optionally        substituted carbocyclyl, optionally substituted heterocyclyl or        optionally substituted heteroaryl; wherein:    -   a. when ring A is unsubstituted phenyl, and ring B is phenyl        substituted by methoxy or ethoxy; then said phenyl of ring B is        not further substituted by oxazolyl;    -   b. when ring A is optionally substituted phenyl or optionally        substituted pyridyl, and ring B is optionally substituted        phenyl; then the portion of the compound represented by        —NH—C(R¹)(R²)(R³) is not —NH(CH₂)-aryl;    -   c. when ring A is optionally substituted phenyl, and ring B is        optionally substituted phenyl or pyrrolyl; then the portion of        the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH(CH₂)C(O)NH₂;    -   d. when ring A is phenyl substituted with 2 or more hydroxyl or        methoxy, and ring B is optionally substituted phenyl; then the        portion of the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH-cycloheptyl;    -   e. when ring A is optionally substituted phenyl and ring B is        optionally substituted phenyl; then R¹ and R³ do not form        2,2,6,6,-tetramethylpiperidin-4-yl;    -   f. when ring A and ring B are optionally substituted phenyl;        then the portion of the compound represented by        —NH—C(R¹)(R²)(R³) is not cysteine, optionally substituted        phenylalanine or leucine or methyl ester thereof;    -   g. when ring A is phenyl or pyridin-3-yl optionally substituted        with one or more substituents selected from halo, methyl or CF₃,        and ring B is phenyl optionally substituted with one or more        substituents selected from halo, methyl, CF₃, methoxy,        CH═C(phenyl)CN; then the portion of the compound represented by        —NHC(R¹)(R²)(R³) is other than —NH(C₁-C₈        alkylene)-N(R^(a))(R^(a)), —NH-1-(aminomethyl)cyclopentylmethyl,        —NH-4-(aminomethyl)cyclohexylmethyl, wherein each R^(a) is        hydrogen, C₁-C₄ alkyl or two R^(a)s are taken together with the        nitrogen to which they are commonly bound to form morpholin-4-yl        or pipieridin-1-yl;    -   h. when ring A is phenyl, 4-chlorophenyl or 4-methyl phenyl and        ring B is 4-chlorophenyl or 3,4-dichlorophenyl; then the portion        of the compound represented by —NHC(R¹)(R²)(R³) is not        —NH-isopropyl;    -   i. when ring A is unsubstituted phenyl and the portion of the        compound represented by —NHC(R¹)(R²)(R³) is —NH—CH₂CH₂N(CH₃)₂,        —NH—CH₂CH₂-morpholin-4-yl or —NH—CH₂CH₂OH; then ring B is other        than oxadiazole, imidazole, thiazole or oxazole each of which is        substituted with —C(O)NHR^(b), wherein R^(b) is isopropyl,        cyclopropyl or 2-chloro-6-methylphenyl;    -   j. when ring A is phenyl substituted with SO₂OH or SO₂Na and        ring B is phenyl, or when ring B is phenyl substituted with        SO₂OH and ring A is substituted phenyl; then the portion of the        compound represented by —NHC(R¹)(R²)(R³) is not —NH(CH₂)₂OH or        —NH(CH₂)CH(OH)CH₃; and    -   k. the compound is other than:

-   (E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacrylonitrile,

-   4-((4-((furan-2-ylmethyl)amino)-6-(pyridin-4-yl)-1,3,5-triazin-2-yl)amino)phenol,

-   3-(4-((5-aminopentyl)amino)-6-((3-fluorophenyl)amino)-1,3,5-triazin-2-yl)phenol,

-   N²,6-bis(3-fluorophenyl)-N⁴-(piperidin-3-yl)-1,3,5-triazine-2,4-diamine,

-   N²-butyl-6-phenyl-N⁴-(p-tolyl)-1,3,5-triazine-2,4-diamine,    N²-cyclohexyl-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine,

-   (R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-yl)amino)-4-methylbenzamide,

-   2-chloro-4-(methylsulfonyl)-N-[4-(phenylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,

-   N²-(2-methoxyethyl)-N⁴-phenyl-6-[5-[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine,

-   N²-(2-furanylmethyl)-6-phenyl-N⁴-[3-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine,

-   6-(3-methoxyphenyl)-N²-methyl-N⁴-(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,

-   N²-butyl-N⁴-(4-methylphenyl)-6-phenyl-1,3,5-triazine-2,4-diamine,    and

-   4-[[4-(5-chloro-2-methylphenyl)-6-(methylamino)]-1,3,5-triazin-2-yl]amino-benzenemethanol.

Also provided is a compound of Structural Formula I, or apharmaceutically acceptable salt or hydrate thereof:

wherein:

ring A is an optionally substituted 5-6 member monocyclic aryl ormonocyclic heteroaryl;

-   -   ring B is an optionally substituted 5-6 member monocyclic aryl        or monocyclic heteroaryl;    -   R¹ and R³ are each independently selected from hydrogen, C₁-C₄        alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, and CN, wherein any        alkyl portion of R¹ is optionally substituted with —OH, NH₂,        NH(C₁-C₄ alkyl), or N(C₁-C₄ alkyl)₂;    -   R² is selected from: —(C₁-C₆ alkyl), —(C₂-C₆ alkenyl or        alkynyl), —(C₁-C₆ alkylene)-N(R⁶)—(C₁-C₆ alkylene)-O—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-N(R⁶)—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)(R⁶), —(C₁-C₆ alkylene)-N(R⁶)—S(O)₁₋₂—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-N(R⁶)—S(O)₁₋₂—(C₀-C₆ alkyl)-Q, —(C₁-C₆        alkylene)-S(O)₁₋₂—N(R⁶)(R⁶), —(C₁-C₄        alkylene)-S(O)₁₋₂—N(R⁶)—(C₁-C₆ alkylene)-Q, —C(O)N(R⁶)—(C₁-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkyl),        —C(O)N(R⁶)—(C₁-C₆ alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₀-C₆        alkylene)-Q, —(C₁-C₆ alkylene)-O—C(O)—(C₁-C₆ alkyl), —(C₁-C₆        alkylene)-O—C(O)—(C₀-C₆ alkyl)-Q, —(C₁-C₆ alkylene)-O—(C₁-C₆        alkyl), —(C₁-C₆ alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-O—(C₁-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-O—C(O)—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)-O—C(O)—(C₀-C₆        alkylene)-Q, —(C₀-C₆ alkylene)-C(O)N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)N(R⁶)—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)C(O)—(C₁-C₆ alkyl), —(C₁-C₆        alkylene)-N(R⁶)C(O)—(C₀-C₆ alkylene)-Q, —(C₀-C₆        alkylene)-S(O)₀₋₂—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-S(O)₀₋₂—(C₀-C₆ alkylene)-Q, —(C₁-C₆        alkylene)-N(R⁶)—C(O)—N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₆ alkylene)-Q,        —(C₀-C₆ alkylene)-C(O)—(C₁-C₆ alkyl), —(C₀-C₆        alkylene)-C(O)—(C₀-C₆ alkylene)-Q, wherein:    -   any alkyl or alkylene moiety present in R² is optionally        substituted with one or more —OH, —O(C₁-C₄ alkyl) or halo;    -   any terminal methyl moiety present in R² is optionally replaced        with —CH₂OH, CF₃, —CH₂F, —CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;    -   each R⁶ is independently selected from hydrogen and C₁-C₆ alkyl;        and    -   Q is selected from aryl, heteroaryl, carbocyclyl and        heterocyclyl, any of which is optionally substituted; or    -   R¹ and R³ are optionally taken together with the carbon to which        they are attached to form C(═O), or    -   R¹ and R² are optionally taken together to form substituted        carbocyclyl or optionally substituted heterocyclyl, wherein:    -   a. when ring A is unsubstituted phenyl, and ring B is phenyl        substituted by methoxy or ethoxy; then said phenyl of ring B is        not further substituted oxazolyl;    -   b. when ring A is optionally substituted phenyl or optionally        substituted pyridyl; then the portion of the compound        represented by —NH—C(R¹)(R²)(R³) is not —NH(CH₂)-aryl;    -   c. when ring A is optionally substituted phenyl, and ring B is        optionally substituted phenyl or pyrrolyl; then the portion of        the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH(CH₂)C(O)NH₂;    -   d. when ring A is phenyl substituted with 2 or more hydroxyl or        methoxy, and ring B is optionally substituted phenyl; then the        portion of the compound represented by —NH—C(R¹)(R²)(R³) is not        —NH-cycloheptyl;    -   e. when ring A is optionally substituted phenyl and ring B is        optionally substituted phenyl; then R¹ and R³ do not form        2,2,6,6,-tetramethylpiperidin-4-yl;    -   f. when ring A and ring B are optionally substituted phenyl;        then the portion of the compound represented by        —NH—C(R¹)(R²)(R³) is not cysteine, optionally substituted        phenylalanine or leucine;    -   g. when ring A is phenyl or pyridin-3-yl optionally substituted        with one or more substituents selected from halo, methyl or CF₃,        and ring B is phenyl optionally substituted with one or more        substituents selected from halo, methyl or CF₃; then the portion        of the compound represented by —NHC(R¹)(R²)(R³) is other than        —NH(C₁-C₈ alkylene)-N(R^(a))(R^(a)),        —NH-1-(aminomethyl)cyclopentylmethyl,        —NH-4-(aminomethyl)cyclohexylmethyl, wherein each R^(a) is        hydrogen, C₁-C₃ alkyl or two R^(a)s are taken together with the        nitrogen to which they are commonly bound to form morpholin-4-yl        or pipieridin-1-yl;    -   h. when ring A is phenyl, 4-chlorophenyl or 4-methyl phenyl and        ring B is 4-chlorophenyl or 3,4-dichlorophenyl; then the portion        of the compound represented by —NHC(R¹)(R²)(R³) is not        —NH-isopropyl;    -   i. when ring A is unsubstituted phenyl and the portion of the        compound represented by —NHC(R¹)(R²)(R³) is —NH—CH₂CH₂N(CH₃)₂,        —NH—CH₂CH₂-morpholin-4-yl or —NH—CH₂CH₂OH; then ring B is other        than oxadiazole, thiazole or oxazole each of which is        substituted with —C(O)NHR^(b), wherein R^(b) is isopropyl,        cyclopropyl or 2-chloro-6-methylphenyl;    -   j. when ring A is phenyl substituted with SO₂OH or SO₂Na, and        ring B is phenyl; then the portion of the compound represented        by —NHC(R¹)(R²)(R³) is not —NH(CH₂)₂OH or —NH(CH₂)CH(OH)CH₃; and    -   k. the compound is other than:

(E)-3-(4-((4-((3-(diethylamino)propyl)amino)-6-phenyl-1,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-2-phenylacrylonitrile,4-((4-((furan-2-ylmethyl)amino)-6-(pyridin-4-yl)-1,3,5-triazin-2-yl)amino)phenol,3-(4-((5-aminopentyl)amino)-6-((3-fluorophenyl)amino)-1,3,5-triazin-2-yl)phenol,N²,6-bis(3-fluorophenyl)-N⁴-(piperidin-3-yl)-1,3,5-triazine-2,4-diamine,N²-butyl-6-phenyl-N⁴-(p-tolyl)-1,3,5-triazine-2,4-diamine,N²-cyclohexyl-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine, and(R)-3-((4-(3-chlorophenyl)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-yl)amino)-4-methylbenzamide.

In some embodiments, R¹ is independently selected from hydrogen, —CH₃,—CH₂CH₃, —CH₂OH, CN, or R¹ and R³ are taken together to form ═0.

In some embodiments, R¹ and R² are taken together to form carbocyclyl orheterocyclyl, either of which is optionally substituted with up to 3substituents independently selected from halo. C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, —CN, ═O, —OH, and —C(O)C₁-C₄ alkyl.

In some embodiments, R² is —(C₁-C₄ alkyl) optionally substituted withfluoro or —OH; —(C₀-C₄ alkylene)-O—(C₁-C₄ alkyl), —(C₀-C₂alkylene)-N(R⁶)—(C₁-C₆ alkyl), —(C₀-C₂ alkylene)-Q, and —O—(C₀-C₂alkylene)-Q, wherein Q is optionally substituted with up to 3substituents independently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, ═O, —C(O)—C₁-C₄ alkyl, —CN, and halo. In one aspect ofthese embodiments, Q is selected from pyridinyl, tetrahydrofuranyl,cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl,wherein Q is optionally substituted with up to 2 substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, ═O, fluoro,chloro, and bromo. In another aspect of these embodiments, Q is selectedfrom pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl,pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substitutedwith up to 2 substituents independently selected from —CH₃ and ═O.

In some embodiments, R¹ and R² are taken together to form cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl,oxobicyclo[3.1.0]hexanyl, azetidinyl, phenyl and pyridinyl, any of whichis optionally substituted with up to 2 substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, —OH,—C(O)CH₃, fluoro, and chloro.

In some embodiments, ring A is an optionally substituted 6-memberedmonocyclic aryl. In some embodiments, ring A is an optionallysubstituted 5-6 membered heteroaryl. In some embodiments, ring A is anoptionally substituted 6 membered heteroaryl.

In some embodiments, ring A is selected from phenyl, pyrazolyl,oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl,wherein ring A is optionally substituted with up to two substituentsindependently selected from halo, —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, —C₁-C₄hydroxyalkyl, —NH—S(O)₂—(C₁-C₄ alkyl), —S(O)₂NH(C₁-C₄ alkyl), —CN,—S(O)₂—(C₁-C₄ alkyl), C₁-C₄ alkoxy, —NH(C₁-C₄ alkyl), —OH, —OCF₃, —CN,—NH₂, —C(O)NH₂, —C(O)NH(C₁-C₄ alkyl), —C(O)—N(C₁-C₄ alkyl)₂, andcyclopropyl optionally substituted with OH.

In some embodiments, ring A is selected from phenyl, pyrazolyl,oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl,wherein ring A is optionally substituted with up to two substituentsindependently selected from halo, —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, —C₁-C₄hydroxyalkyl, —NH—S(O)₂—(C₁-C₄ alkyl), —S(O)₂NH(C₁-C₄ alkyl), —CN,—S(O)₂—(C₁-C₄ alkyl), C₁-C₄ alkoxy, —NH(C₁-C₄ alkyl), —OH, —CN, and—NH₂.

In some embodiments, ring B is selected from phenyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl,and pyrazinyl, wherein ring B is optionally substituted with up to twosubstituents independently selected from halo, —C₁-C₄ alkyl, —C₂-C₄alkynyl, —C₁-C₄ haloalkyl, —C₁-C₄ hydroxyalkyl, C₃-C₆ cycloalkyl,—(C₀-C₂ alkylene)-O—C₁-C₄ alkyl, —O—(C₁-C₄ alkylene)-C₃-C₆ cycloalkyl,—NH—S(O)₂—(C₁-C₄ alkyl), —S(O)₂NH(C₁-C₄ alkyl), —S(O)₂—NH—(C₃-C₆cycloalkyl), —S(O)₂-(saturated heterocyclyl), —CN, —S(O)₂—(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OH, C(O)—O—(C₁-C₄ alkyl), saturatedheterocyclyl, and —NH₂.

In another embodiment, the compound is a compound having StructuralFormula II:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A′ is selected from phenyl and pyridin-2-yl, wherein ring A′ isoptionally substituted with one or two substituents independentlyselected from chloro, fluoro, —CF₃, —CHF₂, —CH₃, —CH₂CH₃, —CF₂CH₃, —OH,—OCH₃, —OCH₂CH₃, —NH₂, —NH(CH₃), and —N(CH₃)₂;

Ring B′ is selected from pyridin-3-yl, pyridin-4-yl, isoxazoly-4-yl,isoxazol-3-yl, thiazol-5-yl, pyrimidin-5-yl and pyrazol-4-yl, whereinring B′ is optionally substituted with one to two substituentsindependently selected from halo; —CN; —OH; C₁-C₄ alkyl optionallysubstituted with halo, CN or —OH; —S(O)₂—C₁-C₄ alkyl; —S(O)—C₁-C₄ alkyl;—S(O)₂—NH—C₁-C₄ alkyl; —S(O)₂—N(C₁-C₄ alkyl)₂; —S(O)₂-azetidin-1-yl;—O—C₁-C₄ alkyl; —CH₂—O—CH₃, morpholin-4-yl, cyclopropyl,—S(O)₂—NH-cyclopropyl; —C(O)—O—CH₃; and

—C(R^(1a))(R^(2a))(R^(3a)) is selected from C₁-C₆ alkyl optionallysubstituted with halo or —OH; —(C₀-C₁ alkylene)-cycloalkyl, wherein thealkylene is optionally substituted with methyl and the cycloalkyl isoptionally substituted with halo, —OCH₃ or methyl; saturatedheterocyclyl optionally substituted with halo or methyl; —C(O)—O—C₁-C₆alkyl; —C(O)—(C₀-C₁ alkylene)-cyclopropyl; and C(O)-benzyl.

In certain embodiments of Formula II, ring A′ is selected from2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-hydroxyphenyl,6-aminopyridin-2-yl, 6-chloropyridin-2-yl,6-trifluoromethylpyridin-2-yl, and phenyl.

In certain embodiments of Formula II, ring B′ is selected from2-(morpholin-4-yl)pyridin-4-yl, 2-dimethylaminopyridin-4-yl,3-(2-methyoxyethyl)phenyl, 3,5-difluorophenyl, 3-chlorophenyl,3-cyanomethylphenyl, 3-cyanophenyl, 3-cyclopropylaminosulfonylphenyl,3-dimethylaminosulfonylphenyl, 3-ethylsulfonylphenyl, 3-fluorophenyl,3-methylsulfonylphenyl, 4-fluorophenyl, 5-chloropyridin-3-yl,5-cyanopyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-4-yl,5-fluoropyridin-3-yl, 5-trifluoromethypyridin-3-yl,6-chloropyridin-4-yl, 6-cyanopyridin-4-yl, 6-cyclopropylpyridin-4-yl,6-ethoxypyridin-4-yl, 6-fluoropyridin-3-yl, 6-fluoropyridin-4-yl,6-methylpyridin-4-yl, 6-trifluoromethylpyridin-4-yl, isoxazol-4-yl,phenyl, pyridin-4-yl, and thiazol-5-yl.

In certain embodiments of Formula II, the moiety represented byC(R^(1a))(R^(2a))(R^(3a)) is selected from 2-hydroxycyclopentyl,3-hydroxycyclopentyl, 1-methylcyclopropyl, 2-methylcyclopropyl,3,3-difluorocyclobutyl, bicycloheptanyl, —(CH₂)₃CH₃, —CH(CH₃)—C(CH₃)₃,—CH(CH₃)—CH₂OCH₃, —C(O)—C(CH₃)₃, —C(O)—OC(CH₃)₃, —C(O)CH₂OH,—C(O)—CH(CH₃)₂, —C(O)-1-hydroxycyclopropyl, —C(O)-2-pyrrolidinon-5-yl,—C(O)-2-pyrrolyl, —C(O)CH₂OCH(CH₃)₂, —C(O)-cyclopropyl,—C(O)—CH₂-cyclopropyl, —C(O)—OC(CH₃)₃, —C(O)CH(CH₃)OH,—C(O)-1H-pyrazol-5-yl, —C(O)NHCH₂CH₃, —CH₂CH(CH₃)OCH₃, —CH₂CH₂CH₂OCH₃,—C(O)—OCH₂CH(CH₃)₂, —CH₂CH₂—OCH₃, —C(O)—OCH₂CH₃, —C(O)—CH₂CH₃,—CH(CH₃)—CH(CH₃)₂, —CH₂CH(CH₃)OH, —CH(CH₃)CH₂CH₃, —CH(CH₃)—CH₂CH₃,—CH(CH₃)CH₂OH, —CH₂C(CH₃)₃, —CH(CH₂OH)CH(CH₃)CH₃, —CH(CH₃)C(CH₃)₃,—CH₂C(CH₃)₂CH₂OH, —CH₂CH₂OH, —CH₂CH(CH₃)OH, —CH(CH₃)CH₂OCH₃,—CH₂—CH(CH₃)CH₂OH, —CH₂C(CH₃)₂OCH₃, —CH(C(CH₃)₃)CH₂OH, —CH₂C(CH₃)₂—OH,CH₂C(CH₃)₃, —CH₂CF₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CH₂CF₃,—CH₂CH₂OCH₂CH₃, —CH₂CH(CH₃)—CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CHC(CH₃)₃CH₂OH,—CH(CH₂CH₃)CH₂OH, —CH₂C(CH₃)₂OH, —CH₂-oxetan-2-yl, —CH₂-oxetan-3-yl,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH(CH₃)-cyclopropyl,—C(O)-1-methylcyclopropyl, —C(O)-tetrahydrofuran-2-yl,—CH₂-tetrahydrofuran-2-yl, —C(O)-tetrahydrofuran-3-yl,—CH₂-morpholin-2-yl, —CH₂-1-methyltetrahydrofuran-2-yl, cyclobutyl,3-methoxycyclobutyl, 3-cyclobutanone, cyclohexyl, 4-hydroxycyclohexyl,cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclopentyl, cyclopropyl,ethyl, isopropyl, isobutyl, n-propyl, n-butyl, oxetan-3-yl,oxobicyclohexanyl, tertrahydropyran-4-yl, 3-oxetanyl, 2-oxetanyl,tetrahydropyran-3-yl, 4,4-difluorocyclohexyl, 4-hydroxycyclohexyl,3-hydroxycyclohexyl, 2-hydroxycyclohexyl, 3-tetrahydrofuranyl,1-cyanocyclobutyl, 1-cyanocyclopropyl, 4-methoxycyclobutyl,3-methyl-oxetan-3-yl, bicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.0]hexanyland 3-cyclohex-2-enonyl.

In certain embodiments of Formula II, the moiety represented byC(R^(1a))(R^(2a))(R^(3a)) is selected from 2-hydroxycyclopentyl,2-methylcyclopropyl, 3,3-difluorocyclobutyl, bicycloheptanyl,—(CH₂)₃CH₃, —CH(CH₃)—C(CH₃)₃, —CH(CH₃)—CH₂OCH₃, —C(O)—C(CH₃)₃,—C(O)—CH(CH₃)₂, —C(O)-cyclopropyl, —C(O)—OC(CH₃)₃, —C(O)—OCH₂CH(CH₃)₂,—C(O)—OCH₂CH₃, —CH(CH₃)—CH(CH₃)₂, —CH(CH₃)—CH₂CH₃, —CH₂C(CH₃)₂CH₂OH,CH₂C(CH₃)₃, —CH₂CF₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)—CH₂CH₃, —CH₂CH₂CH(CH₃)₂,—CH₂— cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,isopropyl, oxetan-3-yl, oxobicyclohexanyl, tertrahydropyran-4-yl, andtetrahydropyran-3-yl.

In another embodiment, the compound is a compound having StructuralFormula II:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A′ is selected from phenyl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, oxazol-4-yl, isoxazol-3-yl, thiazol-2-yl, pyridin-3-yland pyridin-2-yl, wherein ring A′ is optionally substituted with one ortwo substituents independently selected from 1-propenyl,-cyclopropyl-OH, chloro, fluoro, —CF₃, —CHF₂, —CH₃, —CH₂CH₃, —CF₂CH₃,—S(O)CH₃, —S(O)₂CH₃, —CH₂OH, —CH(OH)CH₃, —CH(OH)CF₃, —OH, —OCH₃, —OCF₃,—OCH₂CH₃, —C(O)—NH₂, —CH₂NH₂, —NH₂, —NH(CH₃), —CN and —N(CH₃)₂;

Ring B′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl,pyridazin-4-yl, isoxazol-4-yl, isoxazol-3-yl, thiazol-5-yl,pyrimidin-5-yl and pyrazol-4-yl, wherein ring B′ is optionallysubstituted with one to two substituents independently selected fromhalo; —CN; —OH; C₁-C₄ alkyl optionally substituted with halo, CN or —OH;—S(O)₂—C₁-C₄ alkyl; —S(O)—C₁-C₄ alkyl; —S(O)₂—NH—C₁-C₄ alkyl;—S(O)₂—NH—CH₂—CF₃; —S(O)₂—N(C₁-C₄ alkyl)₂; —S(O)₂-azetidin-1-yl;—O—C₁-C₄ alkyl; —CH₂—O—CH₃, morpholin-4-yl, cyclopropyl,cyclopropyl-C₁-C₄ alkyl, cyclopropyl-C₁-C₄ alkoxy, cyclopropyl-CN,—S(O)₂—NH-cyclopropyl; —S(O)₂—NH—CH₂-cyclopropyl; —C(O)—C₁-C₄ alkyl,—C(O)—O—CH₃; and

—C(R^(1a))(R^(2a))(R^(3a)) is selected from C₁-C₆ alkyl optionallysubstituted with halo, —OCH₃, —P(O)₃ ²⁻ or —OH; —(C₀-C₁alkylene)-cycloalkyl, wherein the alkylene is optionally substitutedwith methyl and the cycloalkyl is optionally substituted with —OH,—CH₂OH, halo, —OCH₃ or methyl; saturated or partially saturated —(C₀-C₁alkylene)-heterocyclyl wherein the heterocyclyl is optionallysubstituted with halo, —S(O)₂—CH₂—C(O)—C₁-C₆ alkyl, —S(O)₂—C₁-C₆ alkyl,—C(O)—O—C₁-C₆ alkyl, —C(O)—N(CH₃)₂ or methyl; —C(O)—O—C₁-C₆ alkyl;—C(O)—(C₀-C₁ alkylene)-cyclopropyl; and C(O)-benzyl.

In certain embodiments of Formula II, ring A′ is selected from2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-hydroxyphenyl,3-amidophenyl, 3-methylsulfinylphenyl, 3-methylsulfonylphenyl,3-(1-methanol)phenyl, 3-methanaminephenyl, 3-methoxy-2-fluorophenyl,5-methoxy-2-fluorophenyl, 3-hydroxy-2-fluorophenyl,5-hydroxy-2-fluorophenyl, 5-hydroxy-3-fluorophenyl, 3-methanolphenyl,3,5-dihydroxyphenyl, 3-trifluoromethyl-5-chlorophenyl,3-(1-hydoxy-2,2,2-trifluoroethyl)phenyl, 3-(1-hydoxyethyl)phenyl,3-(1-hydoxycyclopropyl)phenyl, 3-hydroxymethyl-5-phenol, pyridin-2-yl,3-fluoropyridin-2-yl, 3-cyanopyridin-2-yl, 3,6-difluoropyridin-2-yl,3-fluoro-6-methoxypyridin-2-yl, 3-fluoro-6-hydroxypyridin-2-yl,3-fluoro-6-aminopyridin-2-yl, 4-fluoro-6-aminopyridin-2-yl,6-propen-1-ylpyridin-2-yl, 6-prop-1-ylpyridin-2-yl,6-methylaminopyridin-2-yl, 3-fluoro-6-trifluoromethylpyridin-2-yl,4-chloro-6-aminopyridin-2-yl, 4-fluoro-6-aminopyridin-2-yl,4-chloro-6-methoxypyridin-2-yl, 6-aminopyridin-3-yl,2-methoxypyridin-3-yl, 6-aminopyridin-2-yl, 6-chloropyridin-2-yl,6-trifluoromethylpyridin-2-yl, 6-difluoromethylpyridin-2-yl,4-(CH₂OH)-6-trifluoromethyl-pyridin-2-yl,4-(CH₂OH)-6-chloro-pyridin-2-yl,6-(1,1-difluoroethyl)-4-fluoropyridin-2-yl,4-trifluoromethylpyrimidin-2-yl, 4-aminopyrimidin-2-yl,6-trifluoromethyl-4-aminopyrimidin-2-yl,4-trifluoromethyl-6-aminopyrimidin-2-yl, 4-aminopyrimidin-2-yl,2-aminopyrimidin-4-yl, 2-aminopyrimidin-5-yl, 4,6-dichloropyridin-2-yl,3,5-dichlorophenyl, 2,6-difluorophenyl, 2-methyloxazol-4-yl,3-methylisoxazol-5-yl, 4-trifluoromethyl-thiazol-2-yl,4-methylthiazol-2-yl and phenyl.

In certain embodiments of Formula II, ring B′ is selected from2-(morpholin-4-yl)pyridin-4-yl, 2-dimethylaminopyridin-4-yl,3-(2-methyoxyethyl)phenyl, 3,5-difluorophenyl, 3-chlorophenyl,3-cyanomethylphenyl, 3-cyanophenyl, 3-(cyclopropylmethyl)phenyl,3-cyclopropylaminosulfonylphenyl, 3-dimethylaminosulfonylphenyl,3-ethylsulfonylphenyl, 3-fluorophenyl, 3-methylsulfonylphenyl,4-fluorophenyl, 3-(1-hydroxyisopropyl)phenyl,3-methylsulfonyl-5-chlorophenyl, 3-methylsulfonyl-5-fluorophenyl,3-(N-2,2,2,-trifluoroethylaminosulfonyl)phenyl,3-(N-cyclopropyl)benzamide, 5-chloropyridin-3-yl, 5-cyanopyridin-3-yl,5-cyanopyridin-3-yl, 5-cyanopyridin-4-yl, 5-fluoropyridin-3-yl,2-(1-hydroxyisopropyl)pyridin-4-yl, 5-trifluoromethypyridin-3-yl,2-trifluoromethylpyridin-4-yl, 2-difluoromethylpyridin-4-yl,2-chloropyridin-4-yl, 6-chloropyridin-4-yl, 6-cyanopyridin-4-yl,2-cyanopyridin-4-yl, 6-cyclopropylpyridin-4-yl, 6-ethoxypyridin-4-yl,6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 5,6-difluoropyridin-3-yl,6-fluoropyridin-4-yl, 6-methylpyridin-4-yl,2-difluoromethylpyridin-4-yl, 6-trifluoromethylpyridin-4-yl,2-(1-methoxycyclopropyl)pyridin-4-yl, 2-cyclopropylpyridin-4-yl,2-(propan-1-one)pyridin-4-yl, 2-(1-methylcyclopropyl)pyridin-4-yl,2-(1-cyanocyclopropyl)pyridin-4-yl, 2-(1-cyanoisopropyl)pyridin-4-yl,isoxazol-4-yl, phenyl, pyridin-4-yl, picolinat-2-yl, pyrimidin-5-yl,1-propylpyrazol-4-yl, 6-methyl-pyridazin-4-yl, and thiazol-5-yl.

In certain embodiments of Formula II, the moiety represented byC(R^(1a))(R^(2a))(R^(3a)) is selected from 2-hydroxycyclopentyl,3-hydroxycyclopentyl, 1-methylcyclopropyl, 2-methylcyclopropyl,3,3-difluorocyclobutyl, bicycloheptanyl, —(CH₂)₃CH₃, —CH(CH₃)—C(CH₃)₃,—CH(CH₃)—CH₂OCH₃, —C(O)—C(CH₃)₃, —C(O)—OC(CH₃)₃, —C(O)CH₂OH,—C(O)—CH(CH₃)₂, —C(O)-1-hydroxycyclopropyl, —C(O)-2-pyrrolidinon-5-yl,—C(O)-2-pyrrolyl, —C(O)CH₂OCH(CH₃)₂, —C(O)-cyclopropyl,—C(O)—CH₂-cyclopropyl, —C(O)—OC(CH₃)₃, —C(O)CH(CH₃)OH,—C(O)-1H-pyrazol-5-yl, —C(O)NHCH₂CH₃, —CH₂CH(CH₃)OCH₃, —CH₂CH₂CH₂OCH₃,—C(O)—OCH₂CH(CH₃)₂, —CH₂CH₂—OCH₃, —C(O)—OCH₂CH₃, —C(O)—CH₂CH₃,—CH(CH₃)—CH(CH₃)₂, —CH₂CH(CH₃)OH, —CH(CH₃)CH₂CH₃, —CH₂C(CH₃)₂OH,—CH(CH₃)—CH₂CH₃, —CH(CH₃)CH₂OH, —CH₂C(CH₃)₃, —CH(CH₂OH)CH(CH₃)CH₃,—CH(CH₃)C(CH₃)₃, —CH₂C(CH₃)₂—CH₂OH, —CH₂CH₂OH, —CH₂CH(CH₃)OH,—CH(CH₃)CH₂OCH₃, —CH₂—CH(CH₃)CH₂OH, —CH₂C(CH₃)₂OCH₃, —C(CH₃)₂CH₂OH,—CH₂CH(CH₃)OCH₃, —CH(CH₃)CH(CH₃)OH, —CH₂CH(CH₃)CH₂OH, —CH(C(CH₃)₃)CH₂OH,CH(CH₃)C(CH₃)₂OH, —CH₂C(CH₃)₂—OH, CH₂C(CH₃)₃, —CH₂CF₃, —CH₂CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂CH₂CF₃, —CH₂CH₂OCH₂CH₃, —CH₂CH(CH₃)—CH₂CH₃,—CH₂CH₂CH(CH₃)₂, —CH(C(CH₃)₃)CH₂OH, —CH(CH₂CH₃)CH₂OH, —CH₂C(CH₃)₂OH,—CH₂-oxetan-2-yl, —CH₂-oxetan-3-yl, —CH₂-1-methyl-oxetan-3-yl,—CH₂-cyclopropyl, —CH₂-1-hydroxycyclopropyl, —CH₂-cyclobutyl,—CH(CH₃)-cyclopropyl, —C(O)-1-methylcyclopropyl,—C(O)-tetrahydrofuran-2-yl, —CH₂-tetrahydrofuran-2-yl,—CH₂-tetrahydrofuran-3-yl, —C(O)-tetrahydrofuran-3-yl,—CH₂-morpholin-2-yl, —CH₂-1-methyltetrahydrofuran-2-yl, cyclobutyl,3-methoxycyclobutyl, 3-cyclobutanone, cyclohexyl, 4-hydroxycyclohexyl,cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclopentyl, cyclopropyl,ethyl, isopropyl, isobutyl, n-propyl, n-butyl, t-butyl, oxetan-3-yl,oxobicyclohexanyl, tetrahydropyran-4-yl, 3-oxetanyl, 2-oxetanyl,tetrahydropyran-3-yl, 4,4-difluorocyclohexyl, 4-hydroxycyclohexyl,3-hydroxycyclohexyl, 2-hydroxycyclohexyl, 3-tetrahydrofuranyl,1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-methylcyclopropyl,1-(hydroxymethyl)cyclopropyl, 2-methylcyclopropyl, 2-hydroxycyclopropyl,4-methoxycyclobutyl, 3-methyl-oxetan-3-yl, bicyclo[2.2.1]heptanyl,3-oxabicyclo[3.1.0]hex-6-yl, 1-(t-butylcarboxylate)piperidin-4-yl,piperidin-4-yl, 1-(methylcarboxylate)piperidin-4-yl,1-(1-ethanone)piperidin-4-yl, 1-(methylsulfonyl)piperidin-4-yl,1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, thiazol-5-yl,7-oxa-bicyclo[2.2.1]hept-2-yl, tetrahydropyran-4-yl, and3-cyclohex-2-enonyl.

In certain embodiments of Formula II, the moiety represented byC(R^(1a))(R^(2a))(R^(3a)) is selected from 2-hydroxycyclopentyl,2-methylcyclopropyl, 3,3-difluorocyclobutyl, bicycloheptanyl,—(CH₂)₃CH₃, —CH(CH₃)—C(CH₃)₃, —CH(CH₃)—CH₂OCH₃, —C(O)—C(CH₃)₃,—C(O)—CH(CH₃)₂, —C(O)-cyclopropyl, —C(O)—OC(CH₃)₃, —C(O)—OCH₂CH(CH₃)₂,—C(O)—OCH₂CH₃, —CH(CH₃)—CH(CH₃)₂, —CH(CH₃)—CH₂CH₃, —CH₂C(CH₃)₂—CH₂OH,—CH₂C(OH)(CH₃)₃, CH₂C(CH₃)₃, —CH₂CF₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)—CH₂CH₃,—CH₂CH₂CH(CH₃)₂, —CH₂-cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropyl, isopropyl, t-butyl, oxetan-3-yl, oxobicyclohexanyl,tertrahydropyran-4-yl, and tetrahydropyran-3-yl.

In certain embodiments of Formula II, the moiety represented byC(R^(1a))(R^(2a))(R^(3a)) is selected from 2-methylcyclopropyl,—(CH₂)₃CH₃, —CH(CH₃)—C(CH₃)₃, —CH(CH₃)—CH₂OCH₃, —CH(CH₃)—CH(CH₃)₂,—CH(CH₃)—CH₂CH₃, —CH₂C(CH₃)₂—CH₂OH, —CH₂C(OH)(CH₃)₃, CH₂C(CH₃)₃,—CH₂CF₃, —CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂CH(CH₃)—CH₂CH₃, —CH₂CH₂CH(CH₃)₂,—CH₂-cyclopropyl, isopropyl, and t-butyl.

Further embodiments provided herein include combinations of one or moreof the particular embodiments set forth above.

In another embodiment, the compound is selected from any one of thecompounds set forth in Table 1, below.

TABLE 1 Representative Compounds Cmpd No Structure 100

103

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

126

128

129

130

132

133

135

137

139

140

141

143

145

146

147

148

149

150

151

154

155

156

158

159

160

162

165

167

168

169

170

172

173

174

175

176

177

178

179

181

182

183

184

185

186

187

188

189

190

191

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

334

335

336

337

340

341

342

343

344

345

346

347

348

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

374

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

450

451

452

454

455

456

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

521

522

523

524

526

527

528

529

530

531

532

533

534

535

536

537

538

540

541

542

543

544

545

546

547

548

549

550

551

552

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

576

577

578

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

644

645

646

647

648

649

650

651

652

653

654

655

657

658

660

662

663

664

665

667

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

689

690

691

692

693

694

695

696

697

698

699

Included herein are also methods for making compounds of Formula I or acompound of any one of the embodiments described herein comprisingreacting

with

In some embodiments, the preceding methods comprise step (1) reacting

with

to give

and step (2) reacting

with

In other embodiments, the preceding methods comprise step (1) reacting

with

to give

step (2) reacting

with

to give

and step (3) reacting

Also included are methods for making compounds of Formula I or acompound of any one of the embodiments described herein comprisingreacting

with

In some embodiments, the preceding methods comprise step (1) reacting

with

to give

and step (2) reacting

with

In other embodiments, the preceding methods wherein R¹ and R³ are takentogether with the carbon atom to form C(═O), comprise step (1) reacting

with NH₃ to give

and step (2) reacting

with R²C(O)Cl or R²C(O)OMe.

Also included are methods for making compounds of Formula I or acompound of any one of the embodiments described herein comprisingreacting

with

In some embodiments, the preceding methods comprise step (1) reacting

with

to give

and step (2) reacting

with

Also included are methods for making compounds of Formula I or acompound of any one of the embodiments described herein comprisingreacting

with

In some embodiments, the preceding methods comprise step (1) reacting

with NH₃ to give

and step (2) reacting

with

Also included are methods for making compounds of Formula I or acompound of any one of the embodiments described herein comprisingreacting

with

In some embodiments, the preceding methods comprise step (1) reacting

with

to give

and step (2) reacting

with

In other embodiments, the preceding methods comprise step (1) converting

step (2) reacting

with

to give

and step (3) reacting

with

The compounds of one aspect of this invention may contain one or moreasymmetric centers and thus occur as racemates, racemic mixtures,scalemic mixtures, and diastereomeric mixtures, as well as singleenantiomers or individual stereoisomers that are substantially free fromanother possible enantiomer or stereoisomer. The term “substantiallyfree of other stereoisomers” as used herein means a preparation enrichedin a compound having a selected stereochemistry at one or more selectedstereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,96%, 97%, 98%, or 99%. The term “enriched” means that at least thedesignated percentage of a preparation is the compound having a selectedstereochemistry at one or more selected stereocenters. Methods ofobtaining or synthesizing an individual enantiomer or stereoisomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

In certain embodiments, the compound of Formula I or II is enriched fora structure or structures having a selected stereochemistry at one ormore carbon atoms. For example, the compound is enriched in the specificstereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,96%, 97%, 98%, or 99%.

The compounds of Formula I or II may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like. For example, the compound isenriched in a specific isotopic form of H, C and/or O by at least about60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

Unless otherwise indicated when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The compounds of one aspect of this invention may also be represented inmultiple tautomeric forms, in such instances, one aspect of theinvention expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented (e.g., alkylation of a ring system may result in alkylationat multiple sites, one aspect of the invention expressly includes allsuch reaction products; and keto-enol tautomers). All such isomericforms of such compounds are expressly included herein.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R²⁺, NHR³⁺, NR⁴⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group that may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Mesylatesof each compound in Table 1 are explicitly included herein. Examples ofsuitable polymeric organic anions include, but are not limited to, thosederived from the following polymeric acids: tannic acid, carboxymethylcellulose.

The compounds provided herein therefore include the compoundsthemselves, as well as their salts, hydrates and their prodrugs, ifapplicable. The compounds provided herein may be modified and convertedto prodrugs by appending appropriate functionalities to enhance selectedbiological properties, e.g., targeting to a particular tissue. Suchmodifications (i.e., prodrugs) are known in the art and include thosewhich increase biological penetration into a given biologicalcompartment (e.g., blood, lymphatic system, central nervous system),increase oral availability, increase solubility to allow administrationby injection, alter metabolism and alter rate of excretion. Examples ofprodrugs include esters (e.g., phosphates, amino acid (e.g., valine)esters), carbamates and other pharmaceutically acceptable derivatives,which, upon administration to a subject, are capable of providing activecompounds. Calcium and sodium phosphates of each compound in Table 1, ifapplicable, are explicitly included herein. Amino acid (e.g., valine)esters of each compound in Table 1, if applicable, are explicitlyincluded herein.

Compositions and Routes of Administration

The compounds utilized in the methods described herein may be formulatedtogether with a pharmaceutically acceptable carrier or adjuvant intopharmaceutically acceptable compositions prior to be administered to asubject. In another embodiment, such pharmaceutically acceptablecompositions further comprise additional therapeutic agents in amountseffective for achieving a modulation of disease or disease symptoms,including those described herein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a subject, together witha compound of one aspect of this invention, and which does not destroythe pharmacological activity thereof and is nontoxic when administeredin doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of one aspect of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, self-emulsifying drug delivery systems (SEDDS) suchas d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions of one aspect of this invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir,preferably by oral administration or administration by injection. Thepharmaceutical compositions of one aspect of this invention may containany conventional non-toxic pharmaceutically-acceptable carriers,adjuvants or vehicles. In some cases, the pH of the formulation may beadjusted with pharmaceutically acceptable acids, bases or buffers toenhance the stability of the formulated compound or its delivery form.The term parenteral as used herein includes subcutaneous,intracutaneous, intravenous, intramuscular, intraarticular,intraarterial, intrasynovial, intrasternal, intrathecal, intralesionaland intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of one aspect of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of one aspect of this invention may alsobe administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of one aspect ofthis invention with a suitable non-irritating excipient which is solidat room temperature but liquid at the rectal temperature and thereforewill melt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of one aspectof this invention is useful when the desired treatment involves areas ororgans readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of one aspect of this invention include, but are notlimited to, mineral oil, liquid petroleum, white petroleum, propyleneglycol, polyoxyethylene polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical composition can be formulatedwith a suitable lotion or cream containing the active compound suspendedor dissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of one aspect of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation.

Topically-transdermal patches are also included in one aspect of thisinvention.

The pharmaceutical compositions of one aspect of this invention may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art. When the compositions of one aspect of thisinvention comprise a combination of a compound of the formulae describedherein and one or more additional therapeutic or prophylactic agents,both the compound and the additional agent should be present at dosagelevels of between about 1 to 100%, and more preferably between about 5to 95% of the dosage normally administered in a monotherapy regimen. Theadditional agents may be administered separately, as part of a multipledose regimen, from the compounds of one aspect of this invention.Alternatively, those agents may be part of a single dosage form, mixedtogether with the compounds of one aspect of this invention in a singlecomposition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofone aspect of this invention will be administered from about 1 to about6 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular subject will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the subject'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of one aspect of this invention maybe administered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Subjects may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

The pharmaceutical compositions described above comprising a compound ofStructural Formula I or II or a compound described in any one of theembodiments herein, may further comprise another therapeutic agentuseful for treating cancer.

Methods of Use

The inhibitory activities of the compounds provided herein against IDH2mutants (e.g., IDH2R140Q and IDH2R172K) can be tested by methodsdescribed in Example 12 or analogous methods.

Provided is a method for inhibiting a mutant IDH2 activity comprisingcontacting a subject in need thereof with a compound of StructuralFormula I or II, a compound described in any one of the embodimentsherein, or a pharmaceutically acceptable salt thereof. In oneembodiment, the cancer to be treated is characterized by a mutant alleleof IDH2 wherein the IDH2 mutation results in a new ability of the enzymeto catalyze the NAPH-dependent reduction of α-ketoglutarate toR(−)-2-hydroxyglutarate in a subject. In one aspect of this embodiment,the mutant IDH2 has an R140X mutation. In another aspect of thisembodiment, the R140X mutation is a R140Q mutation. In another aspect ofthis embodiment, the R140X mutation is a R140W mutation. In anotheraspect of this embodiment, the R140X mutation is a R140L mutation. Inanother aspect of this embodiment, the mutant IDH2 has an R172Xmutation. In another aspect of this embodiment, the R172X mutation is aR172K mutation. In another aspect of this embodiment, the R172X mutationis a R172G mutation.

Also provided are methods of treating a cancer characterized by thepresence of a mutant allele of IDH2 comprising the step of administeringto subject in need thereof (a) a compound of Structural Formula I or II,a compound described in any one of the embodiments herein, or apharmaceutically acceptable salt thereof, or (b) a pharmaceuticalcomposition comprising (a) and a pharmaceutically acceptable carrier.

In one embodiment, the cancer to be treated is characterized by a mutantallele of IDH2 wherein the IDH2 mutation results in a new ability of theenzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate toR(−)-2-hydroxyglutarate in a patient. In one aspect of this embodiment,the mutant IDH2 has an R140X mutation. In another aspect of thisembodiment, the R140X mutation is a R140Q mutation. In another aspect ofthis embodiment, the R140X mutation is a R140W mutation. In anotheraspect of this embodiment, the R140X mutation is a R140L mutation. Inanother aspect of this embodiment, the mutant IDH2 has an R172Xmutation. In another aspect of this embodiment, the R172X mutation is aR172K mutation. In another aspect of this embodiment, the R172X mutationis a R172G mutation. A cancer can be analyzed by sequencing cell samplesto determine the presence and specific nature of (e.g., the changedamino acid present at) a mutation at amino acid 140 and/or 172 of IDH2.

Without being bound by theory, applicants believe that mutant alleles ofIDH2 wherein the IDH2 mutation results in a new ability of the enzyme tocatalyze the NAPH-dependent reduction of α-ketoglutarate toR(−)-2-hydroxyglutarate, and in particular R140Q and/or R172K mutationsof IDH2, characterize a subset of all types of cancers, without regardto their cellular nature or location in the body. Thus, the compoundsand methods of one aspect of this invention are useful to treat any typeof cancer that is characterized by the presence of a mutant allele ofIDH2 imparting such activity and in particular an IDH2 R140Q and/orR172K mutation.

In one aspect of this embodiment, the efficacy of cancer treatment ismonitored by measuring the levels of 2HG in the subject. Typicallylevels of 2HG are measured prior to treatment, wherein an elevated levelis indicated for the use of the compound of Formula I or II or acompound described in any one of the embodiments described herein totreat the cancer. Once the elevated levels are established, the level of2HG is determined during the course of and/or following termination oftreatment to establish efficacy. In certain embodiments, the level of2HG is only determined during the course of and/or following terminationof treatment. A reduction of 2HG levels during the course of treatmentand following treatment is indicative of efficacy. Similarly, adetermination that 2HG levels are not elevated during the course of orfollowing treatment is also indicative of efficacy. Typically, the these2HG measurements will be utilized together with other well-knowndeterminations of efficacy of cancer treatment, such as reduction innumber and size of tumors and/or other cancer-associated lesions,improvement in the general health of the subject, and alterations inother biomarkers that are associated with cancer treatment efficacy.

2HG can be detected in a sample by LC/MS. The sample is mixed 80:20 withmethanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degreesCelsius. The resulting supernatant can be collected and stored at −80degrees Celsius prior to LC-MS/MS to assess 2-hydroxyglutarate levels. Avariety of different liquid chromatography (LC) separation methods canbe used. Each method can be coupled by negative electrospray ionization(ESI, −3.0 kV) to triple-quadrupole mass spectrometers operating inmultiple reaction monitoring (MRM) mode, with MS parameters optimized oninfused metabolite standard solutions. Metabolites can be separated byreversed phase chromatography using 10 mM tributyl-amine as an ionpairing agent in the aqueous mobile phase, according to a variant of apreviously reported method (Luo et al. J Chromatogr A 1147, 153-64,2007). One method allows resolution of TCA metabolites: t=0, 50% B; t=5,95% B; t=7, 95% B; t=8, 0% B, where B refers to an organic mobile phaseof 100% methanol. Another method is specific for 2-hydroxyglutarate,running a fast linear gradient from 50%-95% B (buffers as defined above)over 5 minutes. A Synergi Hydro-RP, 100 mm×2 mm, 2.1 μm particle size(Phenomonex) can be used as the column, as described above. Metabolitescan be quantified by comparison of peak areas with pure metabolitestandards at known concentration. Metabolite flux studies from¹³C-glutamine can be performed as described, e.g., in Munger et al. NatBiotechnol 26, 1179-86, 2008.

In one embodiment 2HG is directly evaluated.

In another embodiment a derivative of 2HG formed in process ofperforming the analytic method is evaluated. By way of example such aderivative can be a derivative formed in MS analysis. Derivatives caninclude a salt adduct, e.g., a Na adduct, a hydration variant, or ahydration variant which is also a salt adduct, e.g., a Na adduct, e.g.,as formed in MS analysis.

In another embodiment a metabolic derivative of 2HG is evaluated.Examples include species that build up or are elevated, or reduced, as aresult of the presence of 2HG, such as glutarate or glutamate that willbe correlated to 2HG, e.g., R-2HG.

Exemplary 2HG derivatives include dehydrated derivatives such as thecompounds provided below or a salt adduct thereof:

In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60,70, 80 or 90% of the tumor cells carry an IDH2 mutation, and inparticular an IDH2 R140Q, R140W, or R140L and/or R172K or R172Gmutation, at the time of diagnosis or treatment.

In another embodiment, one aspect of the invention provides a method oftreating a cancer selected from glioblastoma (glioma), myelodysplasticsyndrome (MDS), myeloproliferative neoplasia (MPN), acute myelogenousleukemia (AML), sarcoma, melanoma, non-small cell lung cancer,chondrosarcoma, cholangiocarcinomas or angioimmunoblastic lymphoma in apatient by administering to the patient a compound of Formula I orFormula II in an amount effective to treat the cancer. In a morespecific embodiment the cancer to be treated is glioma, myelodysplasticsyndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenousleukemia (AML), melanoma, chondrosarcoma, or angioimmunoblasticnon-Hodgkin's lymphoma (NHL).

2HG is known to accumulate in the inherited metabolic disorder2-hydroxyglutaric aciduria. This disease is caused by deficiency in theenzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to α-KG(Struys, E. A. et al. Am J Hum Genet 76, 358-60 (2005)). Patients with2-hydroxyglutarate dehydrogenase deficiencies accumulate 2HG in thebrain as assessed by MRI and CSF analysis, develop leukoencephalopathy,and have an increased risk of developing brain tumors (Aghili, M.,Zahedi, F. & Rafiee, J Neurooncol 91, 233-6 (2009); Kolker, S.,Mayatepek, E. & Hoffmann, G. F. Neuropediatrics 33, 225-31 (2002);Wajner, M., Latini, A., Wyse, A. T. & Dutra-Filho, C. S. J Inherit MetabDis 27, 427-48 (2004)). Furthermore, elevated brain levels of 2HG resultin increased ROS levels (Kolker, S. et al. Eur J Neurosci 16, 21-8(2002); Latini, A. et al. Eur J Neurosci 17, 2017-22 (2003)),potentially contributing to an increased risk of cancer. The ability of2HG to act as an NMDA receptor agonist may contribute to this effect(Kolker, S. et al. Eur J Neurosci 16, 21-8 (2002)). 2HG may also betoxic to cells by competitively inhibiting glutamate and/or αKGutilizing enzymes. These include transaminases which allow utilizationof glutamate nitrogen for amino and nucleic acid biosynthesis, andαKG-dependent prolyl hydroxylases such as those which regulateHif1-alpha levels.

Thus, according to another embodiment, one aspect of the inventionprovides a method of treating 2-hydroxyglutaric aciduria, particularlyD-2-hydroxyglutaric aciduria, in a patient by administering to thepatient a compound of Structural Formula I or II or a compound describedin any one of the embodiments described herein.

Treatment methods described herein can additionally comprise variousevaluation steps prior to and/or following treatment with a compound ofStructural Formula I or II or a compound described in any one of theembodiments described herein.

In one embodiment, prior to and/or after treatment with a compound ofStructural Formula I or II or a compound described in any one of theembodiments described herein, the method further comprises the step ofevaluating the growth, size, weight, invasiveness, stage and/or otherphenotype of the cancer.

In one embodiment, prior to and/or after treatment with a compound ofFormula I or II or a compound described in any one of the embodimentsdescribed herein, the method further comprises the step of evaluatingthe IDH2 genotype of the cancer. This may be achieved by ordinarymethods in the art, such as DNA sequencing, immuno analysis, and/orevaluation of the presence, distribution or level of 2HG.

In one embodiment, prior to and/or after treatment with a compound ofFormula I or II or a compound described in any one of the embodimentsdescribed herein, the method further comprises the step of determiningthe 2HG level in the subject. This may be achieved by spectroscopicanalysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRSmeasurement, sample analysis of bodily fluid, such as serum or spinalcord fluid analysis, or by analysis of surgical material, e.g., bymass-spectroscopy.

Combination Therapies

In some embodiments, the methods described herein comprise theadditional step of co-administering to a subject in need thereof asecond therapy e.g., an additional cancer therapeutic agent or anadditional cancer treatment. Exemplary additional cancer therapeuticagents include for example, chemotherapy, targeted therapy, antibodytherapies, immunotherapy, and hormonal therapy. Additional cancertreatments include, for example: surgery, and radiation therapy.Examples of each of these treatments are provided below.

The term “co-administering” as used herein with respect to an additionalcancer therapeutic agents means that the additional cancer therapeuticagent may be administered together with a compound of one aspect of thisinvention as part of a single dosage form (such as a composition of oneaspect of this invention comprising a compound of one aspect of theinvention and an second therapeutic agent as described above) or asseparate, multiple dosage forms. Alternatively, the additional cancertherapeutic agent may be administered prior to, consecutively with, orfollowing the administration of a compound of one aspect of thisinvention. In such combination therapy treatment, both the compounds ofone aspect of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of one aspect of this invention, comprising both a compoundof one aspect of the invention and a second therapeutic agent, to asubject does not preclude the separate administration of that sametherapeutic agent, any other second therapeutic agent or any compound ofone aspect of this invention to said subject at another time during acourse of treatment. The term “co-administering” as used herein withrespect to an additional cancer treatment means that the additionalcancer treatment may occur prior to, consecutively with, concurrentlywith or following the administration of a compound of one aspect of thisinvention.

In some embodiments, the additional cancer therapeutic agent is achemotherapy agent. Examples of chemotherapeutic agents used in cancertherapy include, for example, antimetabolites (e.g., folic acid, purine,and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitorsand others), and hypomethylating agents (e.g., decitabine(5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine(5-azacytidine), 5-flouro-2′-deoxycytidine, 5,6-dihydro-5-azacytidineand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan,Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide,Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine,Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and othercytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy.

In some embodiments, the additional cancer therapeutic agent is adifferentiation agent. Such differentiation agent includes retinoids(such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid,13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR));arsenic trioxide; histone deacetylase inhibitors HDACs (such asazacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate));hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA));vitamin D; and cytokines (such as colony-stimulating factors includingG-CSF and GM-CSF, and interferons).

In some embodiments the additional cancer therapeutic agent is atargeted therapy agent. Targeted therapy constitutes the use of agentsspecific for the deregulated proteins of cancer cells. Small moleculetargeted therapy drugs are generally inhibitors of enzymatic domains onmutated, overexpressed, or otherwise critical proteins within the cancercell. Prominent examples are the tyrosine kinase inhibitors such asAxitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib,gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib,Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitorssuch as Alvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein, e.g., a biguanide such as metformin orphenformin, preferably phenformin.

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

In some embodiments, the additional cancer therapeutic agent is animmunotherapy agent. Cancer immunotherapy refers to a diverse set oftherapeutic strategies designed to induce the subject's own immunesystem to fight the tumor. Contemporary methods for generating an immuneresponse against tumors include intravesicular BCG immunotherapy forsuperficial bladder cancer, and use of interferons and other cytokinesto induce an immune response in renal cell carcinoma and melanomasubjects.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compound orcomposition described herein.

In some embodiments, the additional cancer therapeutic agent is ahormonal therapy agent. The growth of some cancers can be inhibited byproviding or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers. Removing or blocking estrogen or testosterone is often animportant additional treatment. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeuticallybeneficial. In some embodiments, the hormonal therapy agents can be usedin combination with a compound or a composition described herein.

Other possible additional therapeutic modalities include imatinib, genetherapy, peptide and dendritic cell vaccines, synthetic chlorotoxins,and radiolabeled drugs and antibodies.

EXAMPLES Abbreviations

anhy.—anhydrous aq.—aqueous min—minute(s) mL—millilitermmol—millimole(s) mol—mole(s) MS—mass spectrometry NMR—nuclear magneticresonance TLC—thin layer chromatography HPLC—high-performance liquidchromatography Hz—hertz δ—chemical shift J—coupling constant s—singletd—doublet t—triplet q—quartet m—multiplet br—broad qd—quartet ofdoublets dquin—doublet of quintets dd—doublet of doublets dt—doublet oftriplets CHCl₃—chloroform DCM—dichloromethane DMF—dimethylformamideEt₂O—diethyl ether EtOH—ethyl alcohol EtOAc—ethyl acetate MeOH—methylalcohol MeCN—acetonitrile PE—petroleum ether THF—tetrahydrofuranAcOH—acetic acid HCl—hydrochloric acid H₂SO₄—sulfuric acidNH₄Cl—ammonium chloride KOH—potassium hydroxide NaOH—sodium hydroxideK₂CO₃—potassium carbonate Na₂CO₃—sodium carbonate TFA—trifluoroaceticacid Na₂SO₄—sodium sulfate NaBH₄—sodium borohydride NaHCO₃—sodiumbicarbonate LiHMDS—lithium hexamethyldisilylamide NaHMDS—sodiumhexamethyldisilylamide LAH—lithium aluminum hydride NaBH₄—sodiumborohydride LDA—lithium diisopropylamide Et₃N—triethylamineDMAP—4-(dimethylamino)pyridine DIPEA—N,N-diisopropylethylamineNH₄OH—ammonium hydroxideEDCI—1-ethyl-3-(3-dimethylaminopropyl)carbodiimideHOBt—1-hydroxybenzotriazoleHATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra- methyluroniumBINAP—2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl

In the following examples, reagents were purchased from commercialsources (including Alfa, Acros, Sigma Aldrich, TCI and Shanghai ChemicalReagent Company), and used without further purification. Nuclearmagnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR(Brucker, Switzerland). Chemical shifts were reported in parts permillion (ppm, δ) downfield from tetramethylsilane. Mass spectra were runwith electrospray ionization (ESI) from a Waters LCT TOF MassSpectrometer (Waters, USA).

For exemplary compounds disclosed in this section, the specification ofa stereoisomer (e.g., an (R) or (S) stereoisomer) indicates apreparation of that compound such that the compound is enriched at thespecified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or99%. The chemical name of each of the exemplary compound described belowis generated by ChemDraw software.

Example 1 Preparation of Compounds of Formula I Wherein Ring A isPhenyl, and —C(R¹)(R²)(R³) is Isopropyl

The compounds of this Example are prepared by general Scheme 1, setforth below.

Example 1, Step 1 Preparation of 2,4-dichloro-6-phenyl-1,3,5-triazine(2)

To a solution of 2,4,6-trichloro-[1,3,5]triazine (1, 120 g, 0.652 mol)in anhydrous THF (1200 mL) was added phenylmagnesium bromide (217 mL,0.651 mol, 3 M in ether) dropwise at −10 to −0° C. under N₂ protection.After the addition, the mixture was warmed to room temperature andstirred for 2 hrs. The reaction was cooled to 0° C. and quenched byaddition of saturated NH₄Cl (200 mL), then extracted with ethyl acetate.The organic layer was dried, concentrated and purified via columnchromatography (eluted with petroleum ether) to afford2,4-dichloro-6-phenyl-1,3,5-triazine as a white solid. ¹H NMR (CDCl₃) δ7.51-7.55 (m, 2H), 7.64-7.67 (m, 1H), 8.49-8.63 (m, 2H).

Example 1, Step 2 Preparation of4-chloro-N-isopropyl-6-phenyl-1,3,5-triazin-2-amine (3)

To a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (2; 20 g, 0.089mol) in anhydrous THF (150 mL) was added dropwise a solution ofisopropylamine (5.25 g, 0.089 mol) in THF (10 mL) at room temperaturevia syringe under N₂. After the addition, the mixture was stirred atroom temperature under N₂ for 16 hrs. The reaction was quenched by water(150 mL) and extracted with ethyl acetate. The organic layer was dried,concentrated and purified via SiO₂ chromatography to afford4-chloro-N-isopropyl-6-phenyl-1,3,5-triazin-2-amine (3) as white solid.

¹H NMR (CDCl₃) δ 1.17-1.24 (m, 6H), 4.16-4.35 (m, 1H), 5.46-5.54 (m,1H), 7.18-7.50 (m, 3H0, 8.31 (dd, J₁=8.4 Hz, J₂=34.4 Hz, 2H).

Example 1, Step 3 (Procedure A) Preparation of Compound 178N-(3-Fluoro-phenyl)-N′-isopropyl-6-phenyl-[1,3,5]triazine-2,4-diamine

A mixture of (4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-isopropyl-amine (3;200 mg, 0.806 mmol) and 3-fluoro-phenylamine (135 mg, 1.215 mmol) inanhydrous THF was stirred at room temperature for 16 hrs. The reactionwas quenched by water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated andpurified by a standard method to giveN-(3-fluoro-phenyl)-N′-isopropyl-6-phenyl-[1,3,5]triazine-2,4-diamine.

¹H NMR (METHANOL-d₄) δ 8.37-8.33 (m, 2H), 7.87-7.84 (m, 1H), 7.52-7.48(m, 5H), 7.27-7.25 (m, 1H), 6.73-6.69 (m, 1H), 4.24 (m, 1H), 1.16 (d,J=6.4 Hz, 6H). LC-MS: m/z 323.9 (M+H)⁺. Other compounds produced by Step3, Procedure A of this example using the appropriate reagent 4 are setforth below.

Compound 195N²-isopropyl-N⁴-(3-(methoxymethyl)phenyl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) 8.40-8.34 (m, 2H) 7.99-7.83 (m, 1H), 7.62-7.60 (m,1H), 7.53-7.44 (m, 3H), 7.31-7.27 (m, 1H), 7.00-6.99 (m, 1H), 4.48 (s,2H) 4.29-4.27 (m, 1H), 3.41 (s, 3H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z350.3 (M+H)⁺.

Compound 1982-(3-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)phenyl)acetonitrile

¹H NMR (METHANOL-d₄) 8.42-8.38 (m, 2H) 8.18-8.11 (m, 1H), 7.61-7.60 (m,1H), 7.52-7.45 (m, 3H), 7.35-7.31 (m, 1H), 7.02-7.00 (m, 1H), 4.34 (m,1H), 3.92 (s, 2H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 345.2 (M+H)⁺.

Compound 2012-(3-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)phenyl)propan-2-ol

¹H NMR (METHANOL-d₄) 8.36-8.35 (m, 2H), 8.06-8.01 (m, 1H), 7.55-7.44 (m,4H), 7.29-7.25 (m, 1H), 7.20-7.18 (m, 1H), 4.46-4.41 (m, 1H), 1.58 (s,6H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 364.1 (M+H)⁺.

Compound 204N-ethyl-3-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)benzenesulfonamide

¹H NMR (METHANOL-d₄) δ 8.86-8.64 (m, 1H), 8.44-8.38 (m, 2H), 7.82-7.72(m, 1H), 7.53-7.44 (m, 5H), 4.37-4.35 (m, 1H), 2.97-2.92 (m, 2H),1.299-1.282 (d, J=6.8 Hz, 6H), 1.09-1.05 (t, 3H). LC-MS: m/z 413.1(M+H)⁺.

Compound 205N²-(3-(ethylsulfonyl)phenyl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.81-8.79 (m, 1H), 8.28-8.26 (m, 2H), 7.82-7.63(m, 6H), 4.45-4.42 (m, 1H), 3.26-3.23 (m, 2H), 1.386-1.369 (d, J=6.8 Hz,6H), 1.27-1.24 (t, 3H). LC-MS: m/z 398.0 (M+H)⁺.

Compound 206N²-isopropyl-N⁴-(3-(isopropylsulfonyl)phenyl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.00-8.97 (m, 1H) 8.45-8.39 (m, 2H), 7.78-7.76(m, 1H), 7.58-7.44 (m, 5H), 4.36-4.31 (m, 1H), 3.32-3.31 (m, 1H),1.31-1.29 (m, 6H). LC-MS: m/z 412.0 (M+H)⁺.

Compound 341N-cyclopropyl-3-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)benzenesulfonamide

¹H NMR (METHANOL-d₄) δ 8.77-8.72 (m, 1H), 8.24-8.22 (m, 2H), 7.67-7.62(m, 6H), 4.48-4.45 (m, 1H), 2.24-2.16 (m, 1H), 1.378-1.362 (d, J=6.4 Hz,6H), 0.53-0.51 (m, 4H). LC-MS: m/z 425.3 (M+H)⁺.

Compound 342N-tert-butyl-3-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)benzenesulfonamide

¹H NMR (METHANOL-d₄) δ 8.88-8.69 (m, 1H), 8.45-8.49 (m, 2H), 7.77-7.70(m, 1H), 7.53-7.44 (m, 5H), 4.40-4.37 (m, 1H), 1.304-1.288 (d, J=6.4 Hz,6H), 1.21 (s, 9H). LC-MS: m/z 441.3 (M+H)⁺.

Compound 3512-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)phenol

¹H NMR (METHANOL-d₄) δ 8.40-8.32 (m, 2H), 8.00-7.99 (m, 1H), 7.57-7.47(m, 3H), 6.97-6.87 (m, 3H), 4.45-4.21 (m, 1H), 1.31 (d, J=6.8 Hz, 6H).LC-MS: m/z 321.9 (M+H).

Example 1, Step 3 (Procedure B) Preparation of Compound 288N²-isopropyl-N⁴-(2-methylpyridin-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

To a solution of (4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-isopropyl-amine(3; 150 mg, 0.6 mmol) in DMSO (2 mL) was added 2-methylpyridin-4-amin(78.4 mg, 0.73 mmol), CsF (310 mg, 1.21 mmol) and DIPEA (230 mg, 1.81mmol). The mixture was stirred at 80° C. for 2 h. The mixture was cooleddown to rt and filtered to remove the solid. The filtrate was purifiedby a standard method to giveN²-isopropyl-N⁴-(2-methylpyridin-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine(110 mg, 57.9%).

¹H NMR (METHANOL-d₄) δ 8.19-8.40 (m, 5H), 7.53-7.58 (m, 3H), 4.30-4.43(m, 1H), 2.66-2.77 (m, 3H), 1.33 (d, J=4.4 Hz, 6H). LC-MS: m/z 321.1(M+H)⁺.

Additional compounds of Formula I were made using the appropriatereagent 4 and following Step 3, Procedure B.

Compound 292N²-(3-fluoropyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 1.34-1.39 (m, 6H), 4.43-4.51 (m, 1H), 7.19-7.25(m, 1H), 7.53-7.65 (m, 3H), 8.53-8.58 (m, 2H), 9.40-9.45 (m, 1H),9.56-9.60 (m, 1H). LC-MS: m/z 325.0 (M+H)⁺.

Compound 298N²-isopropyl-N⁴-(2-morpholinopyridin-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.35-8.37 (m, 2H), 7.76-7.90 (m, 2H), 7.51-7.52(m, 3H), 7.45-7.47 (m, 1H), 4.23-4.49 (m, 1H), 3.82-3085 (m, 4H),3.50-3.51 (m, 4H), 1.30 (d, J=6.4 Hz, 6H). LC-MS: m/z 392.1 (M+H)⁺.

Compound 299N²-(2-(azetidin-1-yl)pyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.38-8.43 (m, 2H), 7.46-7.74 (m, 5H), 6.88-6.90(m, 1H), 4.21-4.25 (m, 4H), 2.53-2.56 (m, 2H), 1.30 (d, J=6.4 Hz, 6H).LC-MS: m/z 362.0 (M+H)⁺.

Example 1, Step 3 (Procedure C) Preparation of Compound 146N-(6-fluoro-pyridin-3-yl)-N′-isopropyl-6-phenyl-[1,3,5]triazine-2,4-diamine

A mixture of (4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-isopropyl-amine (3;400 mg, 1.61 mmol), 6-fluoro-pyridin-3-ylamine (272 mg, 2.43 mmol)Pd(dppf)Cl₂ (120 mg, 0.164 mmol) and t-BuONa (310 mg, 3.23 mmol) wasstirred at 80° C. under N₂ for 2 hrs. The mixture was cooled to roomtemperature and quenched by water, then extracted with ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄, concentratedand purified by a standard method to giveN-(6-fluoro-pyridin-3-yl)-N′-isopropyl-6-phenyl-[1,3,5]triazine-2,4-diamine.

1H NMR (METHANOL-d4) δ 8.41-8.39 (m, 2H), 7.91-7.88 (m, 5H), 7.62-7.45(m, 3H), 5.55-5.20 (m, 1H), 4.44-4.20 (m., 1H), 3.05 (s., 1H), 1.31 (dd,J=4, 400 MHz, 6H). LC-MS: m/z 384.2 (M+H)+

Additional compounds of Formula 1 in the example that were preparedaccording to Example 1, Step 3, Procedure C using the appropriatereagent 4 are set forth below.

Compound 1773-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)-N,N-dimethylbenzenesulfonamide

¹H NMR (METHANOL-d₄) δ 8.99-8.78 (m, 1H), 8.39-8.37 (m, 2H), 7.99-7.97(m, 1H), 7.91-7.65 (m, 1H), 7.54-7.38 (m. 5H), 4.41-4.38 (m, 1H), 2.71(s, 6H), 1.293-1.277 (d, J=6.4 Hz, 6H). LC-MS: m/z 413.1 (M+H)⁺.

Compound 193N²-(5-fluoropyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d4) δ 8.47-8.15 (m, 5H), 7.52-7.44 (m, 3H), 7.24-7.17(m, 1H), 5.37-5.16 (m, 1H), 4.44-4.19 (m., 1H), 3.05 (s., 1H), 1.16 (dd,J=4, 400 MHz, 6H). LC-MS: m/z 325.1 (M+H)⁺

Compound 194N²-(5-chloropyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d4) δ 8.59-8.25 (m, 5H), 7.52-7.45 (m, 3H), 7.39-7.26(m, 1H), 5.44-5.23 (m, 1H), 4.45-4.20 (m., 1H), 3.05 (s., 1H), 1.31 (dd,J=4, 400 MHz, 6H). LC-MS: m/z 340.9 (M+H)⁺

Compound 196N²-(6-fluoropyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.63-8.57 (m, 1H), 8.38-8.35 (m, 3H), 7.51-7.45(m, 3H), 7.05-7.01 (m. 1H), 4.40-4.23 (m, 1H), 1.286-1.273 (d, J=5.2 Hz,6H). LC-MS: m/z 325.2 (M+H)⁺.

Compound 1974-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (METHANOL-d₄) δ 8.56-8.32 (m, 4H), 8.03-8.02 (m, 1H), 7.67-7.57(m. 3H), 4.42-4.33 (m, 1H), 1.36-1.28 (br, 6H). LC-MS: m/z 332.1 (M+H)⁺.

Compound 199N²-(2-chloropyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.43-8.37 (m, 2H), 8.23-8.10 (m, 2H), 7.67-7.66(m, 1H), 7.55-7.45 (m. 3H), 4.27-4.24 (m, 1H), 1.327-1.311 (d, J=6.4 Hz,6H). LC-MS: m/z 341.2 (M+H)⁺.

Compound 200N²-(2-ethoxypyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.41-8.36 (m, 2H), 7.91-7.88 (m, 1H), 7.52-7.45(m. 4H), 7.30-7.29 (m, 1H), 4.30-4.25 (m, 1H), 1.42-1.38 (t, 3H),1.308-1.292 (d, J=6.4 Hz, 6H). LC-MS: m/z 351.2 (M+H)⁺.

Compound 202N²-isopropyl-6-phenyl-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 10.45-10.27 (m, 1H), 8.68-8.28 (m, 4H), 7.99-7.51(m, 5H), 4.17-4.16 (m., 1H), 3.25 (s, 6H), 1.24 (dd, J=4, 400 MHz, 6H).LC-MS: m/z 375.1 (M+H)⁺.

Compound 2105-(4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-ylamino)nicotinonitrile

¹H NMR (METHANOL-d₄) δ 8.75-9.25 (m, 2H), 8.34-8.48 (m, 3H), 7.76-7.51(m, 3H), 4.0-4.58 (m, 1H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 331.9(M+H)⁺.

Compound 223N²-(2-fluoropyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.43-8.37 (m, 2H), 7.99-7.97 (m, 1H), 7.86-7.80(m, 1H), 7.65-7.45 (m. 4H), 4.28-4.22 (m, 1H), 1.315-1.299 (d, J=6.4 Hz,6H). LC-MS: m/z 325.1 (M+H)⁺.

Compound 224N²-(2-(ethylamino)pyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.53-8.49 (m, 1H), 8.42-8.36 (m, 2H), 7.74-7.72(m, 2H), 7.53-7.46 (m, 3H), 7.03-.6.99 (m. 1H), 4.42-4.24 (m, 1H),3.36-3.31 (m, 2H), 1.34-1.16 (m, 9H). LC-MS: m/z 350.0 (M+H)⁺.

Compound 266N²-isopropyl-6-phenyl-N⁴-(pyrimidin-5-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.25-9.30 (m, 2H), 8.78-8.79 (m, 1H), 8.36-8.43(m, 2H), 7.45-7.53 (m, 3H), 4.25-4.62 (m, 1H), 1.31 (d, J=6.4 Hz, 6H).LC-MS: m/z 308.2 (M+H)⁺.

Compound 277N²-(3-(ethylsulfinyl)phenyl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.51-8.32 (m, 3H), 7.76-7.52 (m, 4H), 7.35-7.27(m, 1H), 4.50-4.32 (m, 1H), 3.14-3.03 (m, 1H), 2.94-2.89 (m, 1H), 1.33(d, J=6.0 Hz, 6H), 1.23 (t, J=7.2 Hz, 3H). LC-MS: m/z 382.1 (M+H)⁺.

Compound 281N²-isopropyl-N⁴-(6-methylpyridin-3-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.99-8.83 (m, 1H), 8.40-8.35 (m, 2H), 8.32-8.13(m, 1H), 7.55-7.45 (m, 3H), 7.30-7.28 (m, 1H), 4.46-4.22 (m, 1H), 2.52(s, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 321.2 (M+H)⁺.

Compound 289N²-(6-chloropyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.79-8.86 (m, 1H), 8.25-8.40 (m, 3H), 7.37-7.53(m, 4H), 4.40-4.61 (m, 1H), 1.30 (d, J=6.4 Hz, 6H). LC-MS: m/z 340.9(M+H)⁺.

Compound 293N²-(2-(dimethylamino)pyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.44-8.38 (m, 2H), 7.86-7.79 (m, 2H), 7.54-7.45(m, 3H), 7.02-7.00 (m, 1H), 4.30 (m., 1H), 3.25 (s, 6H), 1.30 (dd, J=8,400 MHz, 6H). LC-MS: m/z 350.1 (M+H)⁺.

Compound 301N²-isopropyl-N⁴-(2-(isopropylamino)pyridin-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

H NMR (DMSO-d₄) δ 1.03-1.09 (m, 12H), 3.57-3.74 (m 1H), 3.99-4.18 (m,1H), 7.00 (br, 1H), 7.34-8.35 (m, 9H), 10.7 (d, 1H). LC-MS: m/z 364(M+H)⁺.

Compound 302N²-isopropyl-N⁴-(2-(methylamino)pyridin-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.42-8.35 (m, 2H), 7.79-7.54 (m, 5H), 7.12-7.10(m, 1H), 4.35 (m., 1H), 3.03 (s, 3H), 1.30 (dd, J=16, 400 MHz, 6H).LC-MS: m/z 336.2 (M+H)⁺.

Compound 303N²-isopropyl-N⁴-(6-(methylamino)pyridin-3-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.50 (m, 1H), 8.25-8.24 (m, 2H), 8.07-8.05 (m,1H), 7.75-7.63 (m, 3H), 7.14-7.11 (m, 1H), 4.35 (m., 1H), 3.07 (s, 3H),1.35 (dd, J=8, 400 MHz, 6H). LC-MS: m/z 336.2 (M+H)⁺.

Compound 308N²-isopropyl-N⁴-(1-methyl-1H-pyrazol-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.49-8.20 (m, 2H), 8.21-8.15 (m, 1H), 7.70-7.50(m, 4H), 4.49-4.25 (m, 1H), 3.91 (s, 3H), 1.33 (d, J=6.8 Hz, 6H). LC-MS:m/z 310.2 (M+H).

Compound 309N²-isopropyl-N⁴-(isoxazol-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.30-9.12 (m, 1H), 8.57 (s, 1H), 8.39-8.34 (m,2H), 7.53-7.47 (m, 3H), 4.41-4.25 (m, 1H), 1.31 (d, J=5.2 Hz, 6H).LC-MS: m/z 297.2 (M+H).

Compound 310N²-(2,6-dimethylpyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.46-8.40 (m, 2H), 8.08-8.06 (m, 2H), 7.57-7.48(m, 3H), 4.47-4.20 (m, 1H), 2.66 (s, 6H), 1.34 (d, J=6.4 Hz, 6H). LC-MS:m/z 335.3 (M+H)⁺.

Compound 311N²-(6-(cyclopropylmethoxy)pyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.56-8.34 (m, 3H), 8.09-8.07 (m, 1H), 7.53-7.45(m, 3H), 6.84-6.81 (m, 1H), 4.41-4.25 (m, 1H), 4.10 (d, J=6.8 Hz, 1H),1.30 (d, J=6.4 Hz, 1H), 1.21-1.20 (m, 1H), 0.65-0.61 (m, 2H), 0.39-0.36(m, 2H). LC-MS: m/z 377.3 (M+H)⁺.

Compound 312N²-(6-isopropoxypyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.59-8.42 (m, 3H), 8.07-8.04 (m, 1H), 7.53-7.45(m, 3H), 6.77-6.75 (m, 1H), 5.19-5.16 (m, 1H), 4.43-4.21 (m, 1H), 1.35(d, J=6.0 Hz, 6H), 1.29 (d, J=6.4 Hz, 6H). LC-MS: m/z 365.2 (M+H)⁺.

Compound 313N²-isopropyl-6-phenyl-N⁴-(thiazol-5-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.59-8.38 (m, 3H), 7.69-7.48 (m, 4H), 4.45-4.23(m, 1H), 1.22 (d, J=6.8 Hz, 6H). LC-MS: m/z 313.1 (M+H)⁺.

Compound 314N²-isopropyl-6-phenyl-N⁴-(3-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.58 (s, 1H), 9.35 (s, 1H), 8.45-8.40 (m, 2H),7.56-7.42 (m, 3H), 7.11 (s, 1H), 4.28-4.25 (m, 1H), 1.25 (d, J=6.4 Hz,6H). LC-MS: m/z 375.2 (M+H)⁺.

Compound 315N²-(2-cyclopropylpyridin-4-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.43-8.34 (m, 2H), 8.21-8.18 (m, 1H), 7.93-7.16(m, 2H), 7.54-7.45 (m. 3H), 4.29-4.26 (m, 1H), 2.15-2.12 (m, 1H),1.319-1.303 (d, J=6.4 Hz, 6H), 1.19-1.18 (m, 2H) 1.03-1.02 (m, 2H).LC-MS: m/z 347.3 (M+H)⁺.

Compound 316N²-(6-cyclopropylpyridin-3-yl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.01-8.98 (m, 1H), 8.40-8.34 (m, 2H), 8.16-8.13(m, 1H), 7.54-7.44 (m, 3H), 7.27-7.25 (m. 1H), 4.27-4.24 (m, 1H),1.299-1.282 (d, J=6.8 Hz, 6H), 1.11-1.06 (m, 2H) 0.97-0.96 (m, 2H).LC-MS: m/z 347.3 (M+H)⁺.

Compound 329N²-isopropyl-6-phenyl-N⁴-(5-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.99-9.03 (m, 2H), 8.36-8.47 (m, 3H), 7.45-7.52(m, 3H), 4.18-4.57 (m, 1H), 1.30 (d, J=6.4 Hz, 6H). LC-MS: m/z 375.2(M+H)⁺.

Compound 332N²-isopropyl-N⁴-(1-methyl-1H-imidazol-4-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.51-8.22 (m, 3H), 7.48-7.38 (m, 3H), 7.28 (s,1H), 4.38-4.12 (m, 1H), 3.83 (s, 3H), 1.18 (d, J=6.4 Hz, 6H). LC-MS: m/z309.9 (M+H).

Compound 129N²-isopropyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) d 14.92 (br. s., 1H), 112.-11.13 (m, 1H), 8.68-8.63(m, 2H), 8.41-8.36 (m, 4H), 8.24-8.10 (m, 1H), 7.63-7.53 (m, 3H),4.34-4.17 (m., 1H), 1.17 (dd, J=4, 400 MHz, 6H). LC-MS: m/z 307.2(M+H)⁺.

Compound 343N²-isopropyl-N⁴-(2-methylpyrimidin-5-yl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) 9.17-9.11 (m, 2H), 8.42-8.35 (m, 2H), 7.55-7.44 (m.3H), 4.26-4.23 (m, 1H), 2.66 (s, 3H), 1.308-1.292 (d, J=6.4 Hz, 6H).LC-MS: m/z 322.2 (M+H)⁺.

Compound 376N²-(3-(azetidin-1-ylsulfonyl)phenyl)-N⁴-isopropyl-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) 8.99-8.86 (m, 1H), 8.44-8.38 (m, 2H), 7.77-7.75 (m,1H), 7.60-7.44 (m. 5H), 4.35-4.32 (m, 1H), 3.82-3.78 (m, 4H), 2.10-2.02(m, 2H), 1.300-1.284 (d, J=6.4 Hz, 6H). LC-MS: m/z 425.2 (M+H)⁺.

Example 2 Preparation of Compounds of Formula I Wherein Ring A isOptionally Substituted Pyridin-2-Yl or Pyrimnidin-2-Yl

The compounds of this Example are prepared by general Scheme 2, setforth below.

Example 2, Step 1 Preparation of 1-phenyl-2-cyanoguanidine (5)

To a solution of NaN(CN)₂ (50 g, 0.5618 mol) in water (430 mL) at 80° C.was added a solution of aniline (26.2 g, 0.28 mol) in water and conc.HCl (132 mL/23.5 mL). The mixture was heated to 90° C. for 16 hours. Themixture was cooled to room temperature and quenched by adding saturatedsodium bicarbonate (317 mL). The mixture was filtered and the filtercake was dried via vacuum to afford 1-phenyl-2-cyanoguanidine as a whitesolid.

¹H NMR (DMSO-d4) δ 6.95 (s, 2H), 7.02-7.06 (m, 1H), 7.26-7.32 (m, 4H),9.00 (s, 1H).

The procedure set forth in Example 2, step 1 was used to produce thefollowing intermediates (5) using the appropriate starting material 4.

1-(3-cyanophenyl-2-cyanoguanidine as a brown solid.

LC-MS: m/z 185.9 (M+H)⁺.

1-methanesulfonyl-benzenyl-2-cyanoguanidine as a pale gray solid.

LC-MS: m/z 238.8 (M+H)⁺.

1-3-fluoro-pyridin-2-cyanoguanidine as a pale solid.

¹H NMR (DMSO-d4) δ 7.42 (s, 2H), 7.85-8.01 (m, 1H), 8.24 (s, 1H), 8.38(s, 1H).

1-3-chloro-pyridin-2-cyanoguanidine as a pale gray solid.

¹H NMR (DMSO-d4) δ 8.06 (s, 1H), 8.29 (s, 1H), 8.47 (s, 1H).

1-2-fluoro-pyridin-2-cyanoguanidine as a brown solid.

¹H NMR (DMSO-d4) δ 7.10-7.20 (m, 1H), 7.95-7.99 (m, 1H), 8.15 (s, 1H).

1-3,5-difluoro-phenyl-2-cyano-guanidine as white solid, which wasdirectly used in the next step without further purification.

LC-MS: m/z 196.8 (M+H)⁺.

Example 2, Step 2 Preparation of1-phenyl-2-isopropylamine-diguanidine(7)

To a mixture of 1-phenyl-2-cyanoguanidine (5.0 g, 0.031 mol) inethanol/water (46 mL/18.4 mL) was added CuSO₄.5H₂O (3.91 g, 0.01563mol), followed by isopropyl amine (5.53 g, 0.03975 mol). The mixture washeated to reflux for 16 hours. To the mixture was added water (137 mL)and aq.HCl (15.5 mL in 93 mL of water) at 25−30° C. The resultantmixture was stirred at r.t. for 30 min. Then Na₂S (12.4 g in 62 mL ofwater) was added and stirred for another 30 min. The insoluble CuS wasfiltered off. The filtrate was cooled to 10° C. and added aqueous NaOH(7 g NaOH in 50 mL water) dropwise. The mixture was extracted withdichloromethane (100 mL×3). The organic layer was combined, dried overNa₂SO₄ and concentrated to give 1-phenyl-2-isopropylamine-diguanidine asa brown solid.

¹H NMR (DMSO-d4) δ 1.25 (d, J=4.8 Hz, 6H), 4.91-4.97 (m, 1H), 7.17-7.39(m, 5H).

The procedure set forth in Example 2, step 2 was used to produce thefollowing intermediates (7) using the appropriate intermediate 5 and theappropriate amine 6.

1-3-cyanophenyl-2-isopropylamine-diguanidine as a brown solid.

LC-MS: m/z 245 (M+H)⁺.

1-methanesulfonyl-2-isopropyl-diguanidine as a pale solid.

LC-MS: m/z 298 (M+H)⁺.

1-3-fluoro-pyridin-2-cyclobutyl-diguanidine as a red solid.

LC-MS: m/z 251 (M+H)⁺.

1-3-chloro-pyridin-2-cyclobutyl-diguanidine as a red solid.

LC-MS: m/z 267 (M+H)⁺.

1-2-fluoro-pyridin-2-cyclobutyl-diguanidine as a red solid.

LC-MS: m/z 250.8 (M+H)⁺.

1-3,5-difluoropneyl-2-isopropyl-diguanidine as a brown solid, which wasused in the next step without further purification.

LC-MS: m/z 256 (M+H)⁺.

Example 2, Step 3 Preparation of Compound 214N-Isopropyl-N′-phenyl-6-pyridin-2-yl-[1,3,5]triazine-2,4-diamine

To a mixture ofN-isopropyl-N′-phenyl-6-pyridin-2-yl-[1,3,5]triazine-2,4-diamine (0.5 g,2.28 mmol) and pyridine-2-carboxylic acid methyl ester (0.312 g, 2.28mmol) in methanol (7 mL) was added NaOMe (0.25 g, 4.56 mmol). Themixture was stirred at r.t. for 16 hours. The mixture was poured intowater and extracted with ethyl acetate (50 mL), dried over Na₂SO₄,concentrated and purified by a standard method to affordN-isopropyl-N′-phenyl-6-pyridin-2-yl-[1,3,5]triazine-2,4-diamine.

¹H NMR (METHANOL-d₄) δ 8.72-8.73 (d, 1H), 8.47-8.49 (d, 1H), 7.97-8.01(t, 1H), 7.77-7.79 (d, 2H), 7.56-7.59 (t, 1H), 7.31-7.35 (t, 2H),7.04-7.07 (t, 1H), 4.40-4.45 (m, 1H), 1.30-1.31 (d, 6H). LC-MS: m/z307.0 (M+H)⁺.

Additional compounds of Formula I set forth below were similarlyproduced following Scheme 2 utilizing the appropriate intermediates andreagents.

Compound 2286-(4-chloropyridin-2-yl)-N²-isopropyl-N⁴-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.63-8.64 (d, 1H), 8.48 (s, 1H), 7.73-7.75 (d,2H), 7.63 (s, 1H), 7.29-7.31 (t, 2H), 7.05-7.10 (t, 1H), 4.21-4.24 (m,1H), 1.27-1.29 (d, 6H). LC-MS: m/z 341.0 (M+H)⁺.

Compound 2296-(6-chloropyridin-2-yl)-N²-isopropyl-N⁴-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.37-8.39 (d, 1H), 7.91-7.95 (t, 1H), 7.72-7.74(d, 2H), 7.56-7.58 (d, 1H), 7.29-7.32 (t, 2H), 7.02-7.04 (t, 1H),4.23-4.29 (m, 1H), 1.27-1.28 (d, 6H). LC-MS: m/z 341.0 (M+H)⁺.

Compound 2306-(3-chloropyridin-2-yl)-N²-isopropyl-N⁴-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.54-8.55 (d, 1H), 8.01-8.03 (d, 1H), 7.70-7.72(d, 1H), 7.50-7.53 (m, 1H), 7.27-7.31 (t, 2H), 7.04 (s, 1H), 4.32-4.40(m, 1H), 1.21-1.30 (m, 6H). LC-MS: m/z 340.9 (M+H)⁺.

Compound 2316-(4-(isopropylamino)-6-(phenylamino)-1,3,5-triazin-2-yl)pyridin-2-ol

¹H NMR (METHANOL-d₄) δ 7.70-7.75 (m, 3H), 7.43-7.47 (d, 1H), 7.28-7.33(t, 2H), 7.02-7.07 (t, 1H), 6.68-6.72 (m, 1H), 4.28-4.39 (m, 1H),1.33-1.35 (d, 6H). LC-MS: m/z 323.0 (M+H)⁺.

Compound 2463-(4-(isopropylamino)-6-(pyridin-2-yl)-1,3,5-triazin-2-ylamino)benzonitrile

¹H NMR (METHANOL-d₄) δ 8.71-8.72 (d, 1H), 8.41-8.51 (m, 2H), 7.90-8.00(m, 2H), 7.44-7.58 (m, 2H), 7.33-7.37 (t, 1H), 4.22-4.27 (m, 1H),1.27-1.33 (m, 6H). LC-MS: m/z 332.0 (M+H)⁺.

Compound 247N²-isopropyl-N⁴-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d6) δ 8.64-8.66 (m, 1H), 8.19 (m, 1H), 7.94 (m, 1H), 7.77(m, 2H), 7.27-7.34 (m, 2H), 7.05 (m, 1H), 4.24-4.49 (m, 1H), 1.30 (d,6H). LC-MS: m/z 375.0 (M+H)⁺.

Compound 270N²-isopropyl-N⁴-phenyl-6-(4-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.99 (d, 1H), 8.76 (m, 1H), 7.89 (m, 1H), 7.79(m, 2H), 7.29-7.39 (m, 2H), 7.05 (m, 1H), 4.21-4.52 (m, 1H), 1.29-1.33(m, 6H). LC-MS: m/z 375 (M+H)⁺.

Compound 2906-(6-aminopyridin-2-yl)-N²-isopropyl-N⁴-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.92-8.03 (m, 1H), 7.72-7.83 (m, 1H), 7.69 (m,2H), 7.29-7.33 (m, 2H), 7.14 (m., 1H), 7.06 (m, 1H), 4.15-4.51 (m, 1H),1.25 (d, 6H). LC-MS: m/z 322.1 (M+H)⁺.

Compound 322N²-cyclobutyl-N⁴-(5-fluoropyridin-3-yl)-6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.3 (s, 1H), 8.69-8.85 (m, 2H), 8.34-8.59 (m, 2H),8.17-8.29 (m, 2H), 7.99 (m, 1H), 7.55 (m, 1H), 4.35-4.70 (m, 1H), 2.31(m, 2H), 2.05 (m, 2H), 1.72 (m, 2H). LC-MS: m/z 337.9 (M+H)⁺.

Compound 3236-(6-chloropyridin-2-yl)-N²-cyclobutyl-N⁴-(5-fluoropyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.80 (s, 1H), 8.52-8.62 (m, 1H),8.27-8.42 (m, 2H), 8.22 (m, 1H), 8.09 (m, 1H), 7.70 (m, 1H), 4.35-4.69(m, 1H), 2.31 (m, 2H), 2.09 (m, 2H), 1.72 (m, 2H). LC-MS: m/z 372.2(M+H)⁺.

Compound 3256-(6-chloropyridin-2-yl)-N²-cyclobutyl-N⁴-(6-fluoropyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.59-8.69 (d, 1H), 8.12-8.51 (m, 3H),8.07 (m, 1H), 7.69 (m., 1H), 7.11-7.24 (m, 1H), 4.32-4.66 (m, 1H), 2.33(m, 2H), 2.06 (m, 2H), 1.72 (m, 2H). LC-MS: m/z 371.9 (M+H)⁺.

Compound 330N²-(5-chloropyridin-3-yl)-N⁴-cyclobutyl-6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.33 (s, 1H), 8.83-9.98 (m, 1H), 8.76 (m, 1H),8.55-8.69 (m, 1H), 8.31-8.52 (m., 1H), 8.18-8.29 (m, 2H), 8.01 (m, 1H),7.57 (m, 1H), 4.35-4.69 (m, 1H), 2.33 (m, 2H), 2.06 (m, 2H), 1.72 (m,2H). LC-MS: m/z 354.2 (M+H)⁺.

Compound 331N²-isopropyl-6-(6-(methylamino)pyridin-2-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.76 (m, 2H), 7.60 (m, 2H), 7.31 (m, 2H), 7.04(m, 1H), 6.64 (m, 1H), 4.19-4.48 (m, 1H), 2.96 (s, 3H), 1.27 (m, 6H).LC-MS: m/z 336.2 (M+H)⁺.

Compound 3446-(6-chloropyridin-2-yl)-N²-(6-fluoropyridin-3-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.21-10.81 (d, 1H), 8.61-8.79 (d, 1H), 8.04-8.51 (m,4H), 7.69-7.81 (m, 1H), 7.12-7.24 (m, 1H), 4.05-4.32 (m, 1H), 1.22 (d,6H). LC-MS: m/z 359.9 (M+H)⁺. 381.9 (M+Na)⁺.

Compound 3266-(6-chloropyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.99 (s, 1H), 8.46-8.47 (d, 1H), 7.96-7.99 (m,1H), 7.74-7.77 (m, 1H), 7.55-7.62 (m, 3H), 4.32-4.50 (m, 1H), 3.18 (s,3H), 1.28-1.32 (d, 6H). LC-MS: m/z 418.9 (M+H)⁺.

Compound 3406-(6-chloropyridin-2-yl)-N₂-(3,5-difluorophenyl)-N₄-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.41-8.45 (t, 1H), 8.00-8.04 (t, 1H), 7.63-7.69(m, 1H), 6.64-6.69 (t, 1H), 4.22-4.27 (m, 1H), 1.29-1.35 (d, 6H). LC-MS:m/z 377.2 (M+H)⁺.

Compound 358N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.99 (s, 1H), 8.60-8.72 (m, 1H), 8.19 (t, 1H),7.81 (d, 1H), 7.77-7.78 (m, 1H), 7.55-7.62 (m, 2H), 4.35-4.47 (m, 1H),3.11-3.18 (m, 3H), 1.33 (d, 6H). LC-MS: m/z 453.2 (M+H)⁺.

Compound 359N²-isopropyl-6-(6-methylpyridin-2-yl)-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.60-9.03 (m, 1H), 8.31 (m, 1H), 7.70-8.05 (m,2H), 7.81 (d, 1H), 7.57-7.63 (m, 2H), 7.45-7.47 (m, 1H), 4.39 (m, 1H),3.12-3.19 (m, 3H), 2.67 (s, 3H), 1.34 (d, 6H). LC-MS: m/z 399.2 (M+H)⁺.

Compound 3606-(6-ethynylpyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.89 (s, 1H), 8.56 (d, 1H), 8.15-8.19 (m, 1H),7.71-7.95 (m, 4H), 4.45 (br., 1H), 4.03 (s, 1H), 3.18 (s, 3H), 1.39 (d,6H). LC-MS: m/z 409.2 (M+H)⁺.

Compound 361N²-isopropyl-6-(6-methoxypyridin-2-yl)-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.55-8.99 (m, 1H), 7.82-8.13 (m, 3H), 7.57-7.64(m, 2H), 6.98 (d, 1H), 4.37-4.41 (m., 1H), 4.07 (s, 3H), 3.16 (s, 3H),1.34 (d, 6H). LC-MS: m/z 414.9 (M+H)⁺, 436.9 (M+Na)⁺.

Compound 363N²-(6-fluoropyridin-3-yl)-N⁴-neopentyl-6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.82 (d, 1H), 8.47-8.54 (m, 1H), 8.40 (d, 1H),8.14-8.17 (m, 1H), 7.83-7.88 (m., 1H), 7.45-7.52 (m, 1H), 7.10-7.20 (m,1H), 6.93-6.99 (m, 1H), 5.40-5.77 (m, 1H), 3.31-3.49 (m, 2H), 1.00 (s,9H). LC-MS: m/z 354.2 (M+H)⁺.

Compound 364N²-isopropyl-6-(6-(methylamino)pyridin-2-yl)-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (CDCl3) δ 10.00-10.31 (br., 1H), 8.61-8.82 (m, 1H), 7.53-8.82 (m,5H), 6.95-7.02 (m, 1H), 4.34 (m., 1H), 3.07 (d, 6H), 1.31-1.37 (m, 6H).LC-MS: m/z 414.2 (M+H)⁺.

Compound 365N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-6-(6-(prop-1-ynyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (Methanol-d4) δ 8.89 (s, 1H), 8.49 (d, 1H), 8.11 (t, 1H),7.80-7.86 (m, 3H), 7.71-7.75 (m., 1H), 4.45 (m, 1H), 3.19 (s, 3H), 2.17(d, 3H), 1.40 (d, 6H). LC-MS: m/z 423.0 (M+H)⁺.

Compound 3666-(6-(difluoromethyl)pyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (Methanol-d4) δ 8.88 (s, 1H), 8.78 (m, 1H), 8.35 (s, 1H), 8.10(m, 1H), 7.82 (t, 2H), 7.71 (t, 1H), 6.70-7.10 (m., 1H), 4.30-4.50 (m,1H), 3.17 (s, 3H), 1.39 (d, 6H). LC-MS: m/z 434.9 (M+H)⁺.

Compound 3956-(6-(1,1-difluoroethyl)pyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (Methanol-d4) δ 8.98 (s, 1H), 8.57 (d, 1H), 8.09 (t, 1H), 7.85(d, 1H), 7.80 (m, 1H), 7.55-7.62 (m, 1H), 4.36-4.39 (m, 1H), 3.14-3.17(m, 3H), 2.11 (t, 3H), 1.32 (d, 6H). LC-MS: m/z 449.3 (M+H)⁺. 471.3(M+Na)⁺.

Compound 3976-(6-cyclopropylpyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.97 (s, 1H), 8.21-8.2 (d, 1H), 7.76-7.80 (t,2H), 7.55-7.61 (m, 2H), 7.25-7.27 (d, 1H), 4.35-4.38 (m, 1H), 3.13 (s,3H), 2.23-2.28 (m, 1H), 1.31-1.32 (d, 6H), 1.02-1.12 (m, 4H). LC-MS: m/z425.3 (M+H)⁺.

Compound 3986-(6-aminopyridin-2-yl)-N²-(3,5-difluorophenyl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.66-7.70 (t, 1H), 7.56-7.60 (t, 1H), 7.49-7.51(d, 2H), 6.70-6.73 (d, 1H), 6.53-6.57 (t, 1H), 4.21-4.24 (m, 1H),1.18-1.31 (m, 6H). LC-MS: m/z 358.3 (M+H)⁺.

Example 3 Preparation of Additional Compounds of Formula I Wherein RingA is Substituted Pyridin-2-yl

The compounds of this Example are prepared by general Scheme 3, setforth below.

Example 3, Step 1 Preparation of 6-chloro-pyridine-2-carboxylic acidmethyl ester (10)

To a solution of 6-chloro-pyridine-2-carboxylic acid (48 g, 0.31 mol) inmethanol (770 ml) was added concentrated HCl (6 ml). The mixture wasstirred at 80° C. for 48 hours then concentrated to remove the volatile.The crude product was diluted with ethyl acetated and washed with Sat.NaHCO₃ solution. The organic layer was dried with anhydrous Na₂SO₄ andconcentrated to give 6-chloro-pyridine-2-carboxylic acid methyl ester asa white solid.

LC-MS: m/z 172.0 (M+H)⁺.

The procedure set forth in Example 3, step 1 was used to produce thefollowing intermediates (10) using the appropriate starting material 9.

6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester.

LC-MS: m/z 206 (M+H)⁺.

Example 3, Step 2 Preparation of6-(6-chloropyridin-2-yl)-1,3,5-triazine-2,4-dione

To a solution of Na (32 g, 0.16 mol) in ethanol (500 mL) was addedmethyl 6-chloropicolinate (32 g, 0.16 mol) and biuret (5.3 g, 0.052mol). The mixture was heated to reflux for 1 hour. Then concentrated togive residue which was poured to water and added Sat.NaHCO₃ solution toadjust pH to 7, the precipitated solid was collected by filtration anddried to give 6-(6-chloropyridin-2-yl)-1,3,5-triazine-2,4-dione as awhite solid.

LC-MS: m/z 225 (M+H)⁺.

The procedure set forth in Example 3, step 2 was used to produce thefollowing intermediates (11) starting with appropriate intermediate 10.

6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione as a palewhite solid.

LC-MS: m/z 259 (M+H)⁺.

6-pyridin-2-yl-1H-1,3,5-triazine-2,4-dione.

¹H NMR (DMSO-d4): δ 11.9-12.5 (s, 1H), 11.3-11.6 (s, 1H), 8.7-8.9 (m,1H), 8.2-8.4 (m, 1H), 8.0-8.2 (m, 1H), 7.6-7.8 (m, 1H).

Example 3, Step 3 Preparation of2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine

To a solution of 6-(pyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (3.0g, 013 mol) in POCl₃ (48 mL) was added PCl₅ (23 g, 0.1 mol). The mixturewas stirred at 100° C. for 2 hours then concentrated to remove thevolatile. The residue was diluted with ethyl acetated and washed withSat.NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄and concentrated to give2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine as a brown solid.

LC-MS: m/z 260.9 (M+H)⁺.

The procedure set forth in Example 3, step 3 together with theappropriate starting intermediate 11 was used to produce the followingintermediates (12).

2, 4-dichloro-6-(6-trifluoromethyl-pyridin-2-yl)-1,3,5-triazine as lightyellow solid.

LC-MS: m/z 294.9 (M+H)⁺.

2,4-Dichloro-6-pyridin-2-yl-[1,3,5]triazine (1.0 g, 80%) as brown solid.

LC-MS: m/z 227.0 (M+H)⁺.

Example 3, Step 4 Preparation of4-chloro-6-(6-chloropyridin-2-yl)-N-isopropyl-1,3,5-triazin-2-amine

To a solution of 2,4-dichloro-6-(pyridin-2-yl)-1,3,5-triazine (2.0 g,0.0077 mol) in anhydrous THF (20 mL) was added isopropyl amine (0.45 g,0.0077 mol). The mixture was stirred at room temperature for 1 hour. Themixture was quenched by water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated to give4-chloro-6-(6-chloropyridin-2-yl)-N-isopropyl-1,3,5-triazin-2-aminewhich was used directly in the next step.

LC-MS: m/z 221.1 (M+H)⁺.

The procedure set forth in Step 4 using the appropriate intermediate 12and amine 6 was used to produce the following intermediates (13).

4-Chloro-6-(6-trifluoromethyl-pyridin-2-yl)-1, 3, 5triazin-2-yl-isopropyl-amine

LC-MS: m/z 318.1 (M+H)⁺.

(4-Chloro-6-pyridin-2-yl-[1,3,5]triazin-2-yl)-isopropyl-amine

LC-MS: m/z 249.9 (M+H)⁺.

4-chloro-6-(6-chloropyridin-2-yl)-N-(oxetan-3-yl)-1,3,5-triazin-2-amine,which was used directly in the next step.

LC-MS: m/z 298.2 (M+H)⁺.

4-Chloro-6-(6-trifluoromethyl-pyridin-2-yl)-1,3,5triazin-2-yl-oxetan-3-yl-amine, which was used directly in the nextstep.

LC-MS: m/z 332.1 (M+H)⁺.

4-chloro-N-((tetrahydrofuran-2-yl)-methyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-aminewhich was used directly in the next step.

LC-MS: 360.1 (M+H)⁺.

[4-Chloro-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-yl]-(3-oxa-bicyclo[3.1.0]hex-6yl)-amine, which was used directly in the next step.

LC-MS: m/z 358.1 (M+H)⁺.

1-[4-Chloro-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol.

LC-MS: 348.0 (M+H)⁺.

Example 3, Step 5 Preparation of6-(6-Chloro-pyridin-2-yl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine-Compound356

To a solution of4-chloro-6-(6-chloropyridin-2-yl)-N-(oxetan-3-yl)-1,3,5-triazin-2-amine(0.23 g, 0.78 mmol) in anhydrous dioxane (3 mL) was added2-trifluoromethyl-pyridin-4-ylamine (0.13 g, 0.78 mmol), t-BuONa (0.15g, 1.56 mmol) and Pd(dppf)Cl₂ (0.057 g, 0.078 mmol). The mixture wasstirred at 80° C. under N₂ for 1 hour. The mixture was quenched by waterand extracted with ethyl acetate. The organic layer was dried withanhydrous Na₂SO₄, concentrated and purified by a standard method to give6-(6-chloro-pyridin-2-yl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine.

¹H NMR (METHANOL-d₄): δ 8.5 (m, 2H), 8.4 (m, 1H), 8.3-8.1 (m, 0.5H),7.96 (m, 1H), 7.85 (m, 0.6H), 7.6 (m, 1H), 5.1-5.5 (m, 1H), 5.0 (m, 2H),4.7 (m, 2H). LC-MS: m/z 424.2 (M+H)⁺.

Additional compounds of Formula I set forth below were similarlyproduced following Scheme 3 utilizing the appropriate intermediates andreagents.

Compound 334N²-isopropyl-6-phenyl-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.65-8.75 (m, 2H), 8.5 (m, 2H), 8.15-8.3 (m,0.5H), 8.0 (m, 1H), 7.82 (m, 0.6H), 4.2-4.6 (m, 1H), 1.3 (d, J=6.4 Hz,6H). LC-MS: m/z 375.0 (M+H)⁺.

Compound 335N²-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.6 (m, 2H), 8.5 (m, 1H), 8.1-8.2 (m, 1H), 7.78(m, 0.7H), 4.24-4.27 (m, 1H), 1.3 (d, J=6.8 Hz, 6H). LC-MS: m/z 444.3(M+H)⁺.

Compound 336N²-(oxetan-3-yl)-6-(pyridin-2-yl)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.7 (m, 1H), 8.46-8.52 (m, 3H), 7.89-8.23 (m,2H), 7.6 (m, 1H), 5.15-5.55 (m, 1H), 5.0 (m, 2H), 4.7 (m, 2H). LC-MS:m/z 390.2 (M+H)⁺.

Compound 337N²-(isoxazol-4-yl)-N⁴-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 9.35-9.05 (m, 1H), 8.6-8.7 (m, 2H), 8.2 (m, 1H),8.0 (m, 1H), 5.2-5.4 (m, 1H), 5.0 (m, 2H), 4.7-4.8 (d, J=6.4 Hz, 6H).LC-MS: m/z 343.2 (M+H)⁺.

Compound 345N²-cyclobutyl-N⁴-(6-fluoropyridin-3-yl)-6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.11 (br.s., 1H), 8.75-8.69 (m, 2H), 8.38-8.32 (m,2H), 8.26-8.06 (m, 1H), 7.98-7.94 (m, 1H), 7.56-7.52 (m, 1H), 7.19-7.11(m, 1H), 4.65-4.39 (m, 1H), 2.31-2.27 (m, 2H), 2.09-2.02 (m, 2H),1.70-1.67 (m, 2H). LC-MS: m/z 338.2 (M+H)⁺.

Compound 363N²-(6-fluoropyridin-3-yl)-N⁴-neopentyl-6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (CDCl₃) δ 8.82 (s., 1H), 8.53-8.41 (m, 1H), 8.41-8.39 (m, 1H),8.17-8.09 (m, 1H), 7.88-7.83 (m, 1H), 7.49-7.42 (m, 1H), 7.25-7.15 (m,1H), 6.99-6.92 (m, 1H), 5.76-4.90 (m, 1H), 3.48-3.31 (m, 2H), 1.01 (s,9H). LC-MS: m/z 354.2 (M+H)⁺.

Compound 3536-(6-chloropyridin-2-yl)-N²-isopropyl-N⁴-(pyrimidin-5-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 9.37 (m, 1H), 8.8 (m, 1H), 8.4 (m, 1H), 7.97 (m,1H), 7.6 (m, 1H), 4.2-4.5 (m, 2H), 1.3 (m, 2H). LC-MS: m/z 390.2 (M+H)⁺.

Compound 3546-(6-chloropyridin-2-yl)-N²-(2-chloropyridin-4-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.41-8.44 (m, 1H), 8.17-8.22 (m, 2H), 7.96-8.0(m, 1H), 7.62-7.66 (m, 2H), 4.2-4.6 (m, 1H), 1.35 (d, J=6.8 Hz, 6H).LC-MS: m/z 376.2 (M+H)⁺.

Compound 3554-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (METHANOL-d₄): δ 8.55-8.7 (m, 3H), 8.0 (m, 2H), 7.65 (m, 1H),4.6-4.25 (m, 1H), 1.35 (d, J=6.4 Hz, 6H). LC-MS: m/z 367.2 (M+H)⁺.

Compound 357N²-(oxetan-3-yl)-N⁴-(thiazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 9.19-8.79 (m, 2H), 8.50-8.40 (m, 1H), 8.25-8.19(m, 1H), 7.93-7.81 (m, 1H), 5.21-5.06 (m, 1H), 5.02-4.90 (m, 1H),4.44-4.38 (m, 1H), 3.83-3.72 (m, 2H). LC-MS: m/z 396.1 (M+H)⁺.

Compound 3671-(4-(6-chloropyridin-2-yl)-6-(5-(trifluoromethyl)pyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.98 (s, 1H), 8.94 (s, 1H), 8.49 (s, 1H),8.41-8.39 (m, 1H), 7.98-7.94 (s, 1H), 7.62-7.60 (m., 1H), 3.53 (s, 2H),1.26 (s., 6H). LC-MS: m/z 440.2 (M+H)

Compound 3681-(4-(6-chloropyridin-2-yl)-6-(2-fluoropyridin-4-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.37-8.33 (m, 1H), 7.94-7.90 (m, 2H), 7.68 (s,1H), 7.54-7.42 (m, 2H), 3.46 (s, 2H), 1.19 (s., 6H). LC-MS: m/z 390.2(M+H)

Compound 377N²-(2-fluoropyridin-4-yl)-N⁴-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.67 (m, 1H), 8.2 (m, 1H), 7.8-8.05 (m, 3H), 7.5(m, 1H), 5.15-5.4 (m, 1H), 5.0 (m, 2H), 4.75 (m, 2H). LC-MS: m/z 408(M+H)⁺.

Compound 378N²-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.7 (m, 1H), 8.6-8.35 (m, 2H), 8.1-8.3 (m,1.4H), 7.85-8.0 (m, 1.7H), 5.4-5.15 (m, 1H), 5.02 (m, 2H), 4.75 (m, 2H).LC-MS: m/z 458.2 (M+H)⁺.

Compound 379N²-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N⁴-(5-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆): δ 10.2-10.8 (m, 1H), 9.0-9.4 (m, 2H), 8.5-8.9 (m, 3H),8.3 (m, 1H), 8.1 (m, 1H), 5.0-5.2 (m, 1H), 4.7 (m, 2H), 4.6 (m, 2H).LC-MS: m/z 458.2 (M+H)⁺.

Compound 380N²-(6-fluoropyridin-3-yl)-N⁴-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.5-8.7 (m, 2H), 8.3-8.55 (m, 2H), 8.2 (m, 1H),7.97 (m, 1H), 7.0-7.15 (m, 1H), 5.1-5.4 (m, 1H), 5.0 (m, 2H), 4.7 (m,2H). LC-MS: m/z 407 (M+H)⁺.

Compound 381N²-(5-fluoropyridin-3-yl)-N⁴-(oxetan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.6-8.7 (m, 3H), 8.1-8.22 (m, 2H), 7.95 (m, 1H),5.1-5.4 (m, 1H), 5.0 (m, 2H), 4.72 (m, 2H). LC-MS: m/z 407 (M+H)⁺.

Compound 3825-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)nicotinonitrile

¹H NMR (METHANOL-d₄) δ 9.12 (s, 1H), 8.95-8.77 (m, 2H), 8.71-8.67 (m,1H), 8.56-8.51 (m, 1H), 8.19-8.15 (m, 1H), 7.88-7.86 (m, 1H), 4.60-4.29(m, 1H), 1.40 (d, J=6.4 Hz, 6H) LC-MS: m/z 367.2 (M+H)⁺.

Compound 3836-(6-chloropyridin-2-yl)-N²-(5-fluoropyridin-3-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.88 (s, 1H), 8.52-8.49 (m, 2H), 8.32-8.30 (m,1H), 8.20-8.16 (m, 1H), 7.89-7.87 (m, 1H), 4.35-4.31 (m, 1H), 1.40 (d,J=6.4 Hz, 6H). LC-MS: m/z 360.1 (M+H)⁺.

Compound 3846-(6-chloropyridin-2-yl)-N²-(2-fluoropyridin-4-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.45-8.41 (m, 1H), 8.02-7.96 (m, 2H), 7.79 (s,1H), 7.63-7.61 (m, 1H), 7.54-7.49 (m, 1H), 4.47-4.24 (m, 1H), 1.32 (d,J=6.4 Hz, 6H). LC-MS: m/z 360.1 (M+H)⁺.

Compound 3851-(4-(6-fluoropyridin-3-ylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.63-8.75 (m, 2H), 8.42-8.56 (m, 1H), 8.26-8.30(q, J=8, 1 H), 8.04-8.06 (d, J=7.2 Hz, 1H), 7.16-7.19 (m, 1H), 3.60-3.68(d, J=32.4 Hz, 2H), 1.35 (s., 6H). LC-MS: m/z 424.2 (M+H)⁺.

Compound 386N²-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-N⁴-(5-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.04-8.96 (m, 2H), 8.68-8.64 (m, 1H), 8.49-8.47(m, 1H), 8.20-8.16 (m, 1H), 7.96-7.94 (d, J=8.0 Hz, 1H), 4.60-4.20 (m,1H), 1.31 (d, J=6.4 Hz, 6H). LC-MS: m/z 444.2 (M+H)⁺.

Compound 3881-(4-(6-chloropyridin-2-yl)-6-(6-fluoropyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.58 (s, 1H), 8.42-8.31 (m, 2H), 8.00-7.98 (m,1H), 7.63-7.61 (m, 1H), 7.09-7.08 (m, 1H), 3.52 (s., 2H), 1.27 (s., 6H).LC-MS: m/z 390.2 (M+H)

Compound 3891-(4-(6-chloropyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.46-7.92 (m, 3H), 7.91-7.52 (m, 3H), 3.98-3.88(m, 1H), 3.52-3.33 (m, 2H), 1.16 (t, J=8.0 Hz, 6H). LC-MS: m/z 426.2(M+H).

Compound 3901-(4-(6-chloropyridin-2-yl)-6-(5-fluoropyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.72 (s, 1H), 8.63-8.43 (m, 2H), 8.16-8.16 (m,1H), 8.03-7.99 (m, 1H), 7.65-7.64 (m, 1H), 3.57 (s, 2H), 1.30 (s, 6H).LC-MS: m/z 390.2 (M+H).

Compound 3911-(4-(6-chloropyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.62-8.17 (m, 3H), 8.00-7.95 (m, 1H), 7.84-7.83(m, 1H), 7.63-7.61 (m, 1H), 3.56 (s, 2H), 1.28 (s, 6H). LC-MS: m/z 440.3(M+H).

Compound 3936-(6-chloropyridin-2-yl)-N²-(2-fluoropyridin-4-yl)-N⁴-(oxetan-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆): δ 10.6-10.8 (m, 2H), 8.8-9.2 (m, 1H), 8.3-8.5 (m, 1H),7.9-8.2 (m, 2.4H), 7.6-7.8 (m, 2.5H), 5.0-5.2 (m, 1H), 4.75 (m, 2H), 4.6(m, 2H). LC-MS: m/z 373 (M+H)⁺.

Compound 3946-(6-chloropyridin-2-yl)-N²-isopropyl-N⁴-(5-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.15-8.70 (s, 2H), 8.49 (s, 1H), 8.43-8.38 (m,1H), 7.98-7.93 (m, 1H), 7.60-7.58 (m, 1H), 4.50-4.18 (m, 1H), 1.30 (d,J=8 Hz, 6H). LC-MS: m/z 410.2 (M+H)⁺.

Compound 3966-(6-chloropyridin-2-yl)-N²-isopropyl-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.86-8.67 (br.s, 1H), 8.48-8.42 (m, 2H),8.23-7.61 (m, 3H), 4.53-4.13 (m, 1H), 1.32 (s, 6H). LC-MS: m/z 410.2(M+H)⁺.

Compound 3996-(6-chloropyridin-2-yl)-N²-(5-fluoropyridin-3-yl)-N⁴-isobutyl-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄) δ 8.67-8.41 (m, 3H), 8.13-8.10 (m, 1H), 8.00-7.97(m, 1H), 7.96-7.62 (m, 1H), 3.42-3.31 (m., 2H), 2.04-2.01 (m., 1H), 1.00(dd, J=4, 400 MHz, 6H). LC-MS: m/z 374.2 (M+H)⁺.

Compound 400N²-(3-(azetidin-1-ylsulfonyl)phenyl)-6-(6-chloropyridin-2-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.93 (s, 1H), 8.47-8.45 (m, 1H), 7.98 (m, 1H),7.63-7.61 (m, 1H), 7.56 (m, 2H), 7.50-7.48 (m, 1H), 4.35 (m, 1H),3.82-3.78 (m., 4H), 2.1-2.06 (m., 2H), 1.32-1.30 (d, J=8 Hz, 6H). LC-MS:m/z 459.9 (M+H)⁺.

Compound 4015-(4-(isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)nicotinonitrile

¹H NMR (METHANOL-d₄) δ: 8.96-8.84 (m, 2H), 8.59-8.54 (m, 1H), 8.42-8.397(m, 1H), 8.11-8.07 (m, 1H), 7.87-7.85 (d, J=8.0 Hz, 1H), 4.47-4.12 (m,1H), 1.21 (d, J=6.8 Hz, 6H). LC-MS: m/z 401.2 (M+H)⁺.

Compound 402N²-(2-fluoropyridin-4-yl)-N⁴-((tetrahydrofuran-2-yl)methyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.69 (t, J=7.4 Hz, 1H), 8.22 (t, J=8.0 Hz, 1H),8.04-7.98 (m, 2H), 7.84 (s, 1H), 7.53 (dd, J=10.8 Hz, 5.2 Hz, 1H),4.23-4.19 (m, 1H), 3.99-3.96 (m, 1H), 3.83-3.78 (m, 1H), 3.70-3.63 (m,2H), 2.12-2.08 (m, 1H), 2.04-1.95 (m, 2H), 1.79-1.72 (m, 1H). LC-MS: m/z436.2 (M+H)⁺.

Compound 4034-(4-((tetrahydrofuran-2-yl)methylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (METHANOL-d₄) δ: 8.68 (t, J=7.2 Hz, 1H), 8.59 (d, J=16.8 Hz, 1H),8.46 (dd, J=14.0 Hz, 5.8 Hz, 2H), 8.21 (t, J=7.8 Hz, 1H), 7.99-7.95 (m,2H), 4.23-4.20 (m, 1H), 3.99-3.93 (m, 1H), 3.84-3.78 (m, 1H), 3.69-3.62(m, 2H), 2.13-2.09 (m, 1H), 2.05-1.98 (m, 2H), 1.79-1.73 (m, 1H). LC-MS:m/z 443.3 (M+H)⁺.

Compound 4044-(4-(isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (METHANOL-d₄) δ: 8.72-8.65 (m, 1H), 8.59 (s, 1H), 8.48 (dd,J=10.4 Hz, 6.0 Hz, 1H), 8.22 (t, J=7.8 Hz, 1H), 7.99-7.94 (m, 2H),4.49-4.25 (m, 1H), 1.31 (d, J=7.6 Hz, 6H). LC-MS: m/z 401.2 (M+H)⁺.

Compound 4055-(4-(2-hydroxy-2-methylpropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)nicotinonitrile

¹H NMR (METHANOL-d₄) δ 9.03-9.12 (m, 1H), 8.70-8.78 (m, 3H), 8.37-8.45(m, 1H), 8.18-8.25 (d, J=7.2 Hz, 1H), 3.62 (s, 2H), 1.35 (s, 6H). LC-MS:m/z 431.1 (M+H)⁺.

Compound 4062-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(5-(trifluoromethyl)pyridin-3-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ 9.00-9.18 (m, 2H), 8.69-8.71 (m, 1H), 8.51-8.54(m, 1H), 8.20-8.22 (m, 1H), 7.98-8.00 (m, 1H), 3.57-3.65 (d, J=30.8 Hz,2H), 1.30 (s, 6H). LC-MS: m/z 474.2 (M+H)⁺.

Compound 4071-(4-(5-fluoropyridin-3-ylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.92 (s, 1H), 8.81-8.83 (m, 1H), 8.53-8.58 (m,3H), 8.26-8.28 (m, 1H), 3.64 (s, 2H), 1.35 (s, 6H). LC-MS: m/z 424.2(M+H)⁺.

Compound 4084-(4-(isobutylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (DMSO-d₄) δ 10.7 (s, 1H), 8.52-8.70 (m, 4H), 8.30-8.34 (m, 1H),8.11-8.13 (m, 1H), 7.93-8.05 (m, 1H), 3.21-3.24 (q, J=6.4 Hz, 2H),1.95-2.00 (m, 1H), 0.96-0.98 (q, J=3.6 Hz, 6H). LC-MS: m/z 415.3 (M+H)⁺.

Compound 4092-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.62-8.68 (m, 2H), 847-8.50 (m, 1H), 8.18-8.21(m, 1H), 7.96-7.98 (m, 1H), 7.82-7.84 (m, 1H), 3.56-3.63 (d, J=28 Hz,2H), 1.30 (s, 6H). LC-MS: m/z 474.3 (M+H)⁺.

Compound 4106-(6-chloropyridin-2-yl)-N²-(6-fluoropyridin-3-yl)-N⁴-(oxetan-3-yl)-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄) δ 8.50-8.31 (m, 3H), 7.89-7.86 (m, 1H), 7.53-7.51(m, 1H), 7.02-7.00 (m, 1H), 5.02-4.90 (m., 1H), 4.88-4.84 (m., 2H),4.61-4.59 (m, 2H) LC-MS: m/z 374.2 (M+H)⁺.

Compound 411N²-(3-oxabicyclo[3.1.0]hexan-6-yl)-N⁴-(5-fluoropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

1H NMR (DMSO-d₆) δ 10.04-10.06 (m, 1H), 8.69-8.91 (m, 1H), 8.47-8.58 (m,2H), 8.32 (t, J=8.0 Hz, 1H), 8.19-8.24 (m., 1H), 8.10-8.12 (m, 1H), 3.98(d., J=8.0 Hz, 2H), 3.69 (d., J=8.0 Hz, 2H), 2.57-2.61 (m, 1H), 1.97 (s,2H). LC-MS: m/z 434.2 (M+H)⁺.

Example 4 Preparation of Compounds of Formula I Wherein Ring A isSubstituted Phenyl

The compounds of this Example are prepared by general Scheme 4, setforth below.

Example 4, Step 1 Preparation of4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine

To a solution of 2,4,6-trichloro-1,3,5-triazine (4.0 g, 0.0217 mol) inTHF (25 mL) was added isopropyl amine (1.27 g, 0.0217 mmol) at 0° C. Themixture was stirred at room temperature for 12 hours. The mixture wasadjusted pH 7 by aq NaHCO₃ and extracted with ethyl acetate (100 mL*2).The combined organic layer was dried over Na₂SO₄, concentrated andpurified by column chromatography to give4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine as a colorless oil.

¹H NMR (CDCl₃) δ 1.24-1.27 (m, 6H), 4.21-4.26 (m, 1H), 5.68 (br s, 1H).

The following intermediates (13) were prepared following the procedureof Step 1 using the appropriate amine 6.

4,6-dichloro-N-(oxetan-3-yl)-1,3,5-triazin-2-amine, which was directlyused in the next step.

¹H NMR (CDCl₃) δ 1.71-1.83 (m, 2H), 1.90-2.04 (m, 2H), 2.37-2.46 (m,2H), 4.46-4.56 (m, 1H), 6.04 (br. 1H).

1-(4,6-Dichloro-[1,3,5]triazin-2-ylamino)-2-methyl-propan-2-ol, whichwas directly used in the next step.

LCMS: m/z 237.0 (M+H)⁺.

4,6-dichloro-N-isobutyl-1,3,5-triazin-2-amine, which was directly usedin the next step.

¹H NMR (CDCl₃) δ 0.85 (d, J=8.6 Hz, 6H), 1.75-1.94 (m, 1H), 3.30-3.33(m, 2H), 6.29 (br, 1H).

Example 4, Step 2 Preparation of1-[4-chloro-6-(2-fluoro-phenyl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

To a mixture of 4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine (1.0 g,4.83 mmol), 3-fluorophenylboronic acid (0.671 g, 0.00483 mol) and Cs₂CO₃(3.15 g, 0.00966 mol) in dioxane/water (12 mL/2.4 mL) was addedPd(PPh₃)₄ (0.56 g, 483 mmol). The mixture was heated to 80° C. for 2hours. The mixture was concentrated and purified by SiO₂ chromatographyto give1-[4-chloro-6-(2-fluoro-phenyl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-olas a white solid.

LCMS: m/z 297.1 (M+H)⁺.

Additional intermediates 15 were prepared by the method of Example 4,step 2 using the appropriate boronic acid 14 and the appropriatestarting intermediate 13.

[4-chloro-6-(3-chloro-phenyl)-[1,3,5]triazin-2-yl]-isopropyl-amine

LCMS: m/z 282.9 (M+H)⁺.

4-chloro-6-(2-fluorophenyl)-N-isopropyl-1,3,5-triazin-2-amine

LCMS: m/z 266.8 (M+H)⁺.

4-chloro-6-(2-chlorophenyl)-N-isopropyl-1,3,5-triazin-2-amine

LCMS: m/z 282.8 (M+H)⁺.

4-chloro-6-(3-fluorophenyl)-N-isopropyl-1,3,5-triazin-2-amine

LCMS: m/z 266.9 (M+H)⁺.

[3-(4-Chloro-6-isopropylamino-[1,3,5]triazin-2-yl)-phenyl]-carbamic acidtert-butyl ester

LCMS: m/z 364.2 (M+H)⁺.

[4-Chloro-6-(3-methoxy-phenyl)-[1,3,5]triazin-2-yl]-isopropyl-amine

LCMS: m/z 279.1 (M+H)⁺.

Example 4, Step 3 (Procedure A) Preparation of Compound 2276-(2-fluorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

A mixture of4-chloro-6-(2-fluorophenyl)-N-isopropyl-1,3,5-triazin-2-amine (290 mg,1.1 mmol), pyridine-4-amine (103 mg, 1.1 mmol), CsF (554 mg, 2.2 mmol)and DIPEA (0.425 g, 3.3 mmol) in DMSO (4 mL) was heated to 80° C. for 2hours. The mixture was filtered and purified by a standard method togive6-(2-fluorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine.

¹H NMR (METHANOL-d₄) δ: 8.32 (t, J=6.2 Hz, 2H), 8.12-8.03 (m, 1H), 7.89(t, J=6.2 Hz, 2H), 7.54-7.49 (m, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.23-7.18(m, 1H), 4.35-4.23 (m, 1H), 1.30-1.26 (m, 6H). LC-MS: m/z 325.0 (M+H)⁺.

The following compound was also made using the procedure of Step 3 andthe appropriate amine 4.

Compound 2266-(2-chlorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.31 (t, J=6.2 Hz, 2H), 7.87 (t, J=6.2 Hz, 2H),7.74-7.65 (m, 1H), 7.50-7.37 (m, 3H), 4.31-4.26 (m, 1H), 1.30-1.24 (m,6H). LC-MS: m/z 341.0 (M+H)⁺.

Example 4, Step 3 (Procedure B) Compound 317N²-cyclobutyl-6-(2-fluorophenyl)-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

A mixture of[4-chloro-6-(2-fluoro-phenyl)-[1,3,5]triazin-2-yl]-cyclobutyl-amine (150mg, 0.538 mmol) and 3-methanesulfonyl-phenylamine (111 mg, 0.648 mmol)in anhydrous THF (10 mL) was stirred at 80° C. for 8 hrs. TLC (petroleumether/ethyl acetate 10/1) indicated the reaction was complete and waterwas added. The mixture was extracted with ethyl acetate and the organiclayer was washed with brine, dried over sodium sulfate. Filtered and thefiltrate was concentrated in vacuo to give crudeN-cyclobutyl-6-(2-fluoro-phenyl)-N′-(3-methane-sulfonyl-phenyl)-[1,3,5]triazine-2,4-diamine,which was purified a standard method to give pureN-cyclobutyl-6-(2-fluoro-phenyl)-N′-(3-methanesulfonyl-phenyl)-[1,3,5]triazine-2,4-diamine.

¹H NMR (METHANOL-d₄) δ: 9.00-8.61 (m, 1H), 8.16-7.76 (m, 1H), 7.62-7.52(m, 3H), 7.30-7.18 (m, 2H), 4.67-4.61 (m, 1H), 3.16 (s, 3H), 2.52-2.38(m, 2H), 2.10-2.01 (m, 2H), 1.88-1.76 (m, 2H). LC-MS: m/z 414.3 (M+H)⁺.

Example 4, Step 3 (Procedure C) Synthesis of Compound 318N-Cyclobutyl-6-(2-fluoro-phenyl)-N′-(5-fluoro-pyridin-3-yl)-[1,3,5]triazine-2,4-diamine

A mixture of[4-chloro-6-(2-fluoro-phenyl)-[1,3,5]triazin-2-yl]-cyclobutyl-amine (300mg, 1.08 mmol), 5-fluoro-pyridin-3-ylamine (145 mg, 1.29 mmol)Pd(dppf)Cl₂ (80 mg, 0.11 mmol) and t-BuONa (208 mg, 2.17 mmol) indioxane (15 mL) was stirred at 80° C. under N₂ for 2 hrs. Cooled to roomtemperature and water was added. Extracted with ethyl acetate and theorganic layer was washed with brine, dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by a standard method to obtainN-cyclobutyl-6-(2-fluoro-phenyl)-N′-(5-fluoro-pyridin-3-yl)-[1,3,5]triazine-2,4-diamine.

¹H NMR (METHANOL-d₄) δ: 8.73-8.44 (m, 2H), 8.08 (d, J=13.1 Hz, 2H), 7.53(br.s., 1H), 7.28-7.19 (m, 2H), 4.58-4.51 (m, 1H), 2.42 (br.s., 2H),2.09 (t, J=9.6 Hz, 2H), 1.80 (br.s., 2H). LC-MS: m/z 355.2 (M+H)⁺.

The following compounds were analogously made according to Example 4,step 3 (procedure C) using the appropriate intermediate 15 and theappropriate amine 4

Compound 1846-(3-fluorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.35-8.31 (m, 2H), 8.26-8.20 (m, 1H), 8.10 (t,J=8.9 Hz, 1H), 7.90 (t, J=6.9 Hz, 2H), 7.55-7.47 (m, 1H), 7.30-7.24 (m,1H), 4.43-4.24 (m, 1H), 1.30 (d, J=6.9 Hz, 6H). LC-MS: m/z 325.0 (M+H)⁺.

Compound 1856-(3-chlorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.38-8.30 (m, 4H), 7.91-7.87 (m, 2H), 7.53-7.43(m, 2H), 4.41-4.23 (m, 1H), 1.30 (d, J=6.2 Hz, 6H). LC-MS: m/z 340.9(M+H)⁺.

Compound 3191-(4-(2-fluorophenyl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ: 8.65 (s, 1H), 8.49-8.38 (m, 1H), 8.19-7.85 (m,2H), 7.62-7.52 (m, 1H), 7.32-7.22 (m, 2H), 3.58-3.56 (m, 2H), 1.29-1.27(m, 6H). LC-MS: m/z 423.3 (M+H)⁺.

Compound 3921-(4-(2-fluorophenyl)-6-(5-(trifluoromethyl)pyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄): δ 8.8-9.1 (m, 2H), 8.48 (m, 1H), 8.1 (m, 1H), 7.5(m, 1H), 7.2-7.3 (m, 2H), 3.5 (m, 2H), 1.25 (m, 6H). LC-MS: m/z 428.3(M+H)⁺.

Compound 3206-(2-fluorophenyl)-N²-(5-fluoropyridin-3-yl)-N⁴-isobutyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.64-8.48 (m, 2H), 8.10-8.04 (m, 2H), 7.55-7.51(m, 1H), 7.29 (t, J=7.6, 1H), 7.29 (t, J=11.0, 1H), 3.32 (br.s., 2H),2.03-1.96 (m, 1H), 1.03-0.96 (m, 6H). LC-MS: m/z 357.2 (M+H)⁺.

Compound 3215-(4-(2-fluorophenyl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)nicotinonitrile

¹H NMR (DMSO-d₆) δ: 10.25-10.14 (m, 1H), 9.14 (t, J=2.40, 1H), 8.89-8.79(m, 1H), 8.62-8.61 (m, 1H), 8.04-7.97 (m, 2H), 7.59-7.56 (m, 1H),7.36-7.31 (m, 1H), 4.25-4.13 (m, 1H), 1.24-1.21 (m, 6H). LC-MS: m/z350.2 (M+H)⁺.

Compound 3694-(4-(2-fluorophenyl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)picolinonitrile

¹H NMR (METHANOL-d₄) δ 8.61-8.59 (m, 1H), 8.48-8.44 (m, 1H), 8.16-8.13(m, 1H), 7.98-7.96 (m, 1H), 7.57-7.54 (m, 1H), 7.32-7.23 (m., 2H),4.29-4.27 (m., 2H), 3.05 (s., 1H), 1.16 (dd, J=4, 400 MHz, 6H). LC-MS:m/z 350.2 (M+H)⁺.

Compound 3706-(2-fluorophenyl)-N²-isopropyl-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.65-8.64 (m, 2H), 8.22-8.18 (m, 1H), 7.90-7.89(m, 1H), 7.72 (m, 2H), 7.45-7.35 (m., 2H), 4.38-4.35 (m., 1H), 1.39 (dd,J=4, 400 MHz, 6H). LC-MS: m/z 393.0 (M+H)⁺.

Compound 3716-(2-fluorophenyl)-N²-(2-fluoropyridin-4-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.20-8.15 (m, 2H), 7.75-7.59 (m, 2H), 7.45-7.38(m, 3H), 4.37-4.35 (m., 1H), 1.37 (dd, J=4, 400 MHz, 6H). LC-MS: m/z342.9 (M+H)⁺.

Compound 3726-(2-fluorophenyl)-N²-isopropyl-N⁴-(5-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.31-8.77 (m, 3H), 8.21 (m, 1H), 7.79 (m, 1H),7.47-7.41 (m., 2H), 4.33-4.32 (m, 1H), 1.37 (dd, J=4, 400 MHz, 6H).LC-MS: m/z 393.0 (M+H)⁺.

Compound 3746-(2-fluorophenyl)-N²-(5-fluoropyridin-3-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.69-8.61 (m, 2H), 8.12-8.05 (m, 2H), 7.57-7.52(m, 1H), 7.31-7.21 (m., 2H), 4.28-4.25 (m, 1H), 1.31 (dd, J=4, 400 MHz,6H). LC-MS: m/z 343.2 (M+H)⁺.

Compound 3876-(2-fluorophenyl)-N²-(6-fluoropyridin-3-yl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.61-8.57 (m, 1H), 8.42-8.37 (m, 1H), 8.04-8.00(m, 1H), 7.55-7.51 (m., 1H), 7.30-7.05 (m, 3H), 4.26-4.23 (m, 1H), 1.29(dd, J=4, 400 MHz, 6H). LC-MS: m/z 342.9 (M+H)⁺.

Preparation of1-[4-(3-Amino-phenyl)-6-(pyridin-4-ylamino)-[1,3,5]triazin-2-yl-amino]-2-methyl-propan-2-olCompound 327

To a mixture of1-[4-(3-N-(BOC-amino)-phenyl)-6-(pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol(100.2 mg, 0.24 mmol) in ethyl acetate (1 mL) was added HCl/ethylacetate (4 mL) at 0° C. under N₂. The mixture was stirred at r.t. for 2hours. TLC (petroleum ether/ethyl acetate=3:1) showed that the reactionwas complete. The mixture was concentrated to give a residue, which waspurified by a standard method to give1-[4-(3-amino-phenyl)-6-(pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol.¹H NMR (METHANOL-d₄) δ: 8.44-8.40 (m, 2H), 8.17-8.12 (m, 2H), 7.83-7.72(m, 2H), 7.22 (t, J=7.6 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 4.45-4.26 (m,1H), 1.31 (d, J=6.5 Hz, 6H). LC-MS: m/z 322.2 (M+H)⁺.

Preparation of3-[4-Isopropylamino-6-(pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenolCompound 328

To a mixture ofN-isopropyl-6-(3-methoxy-phenyl)-N′-pyridin-4-yl-[1,3,5]triazine-2,4-diamine(200 mg, 0.6 mmol) in DCM (10 mL) was added BBr₃ (60 mg, 0.6 mol) at−78° C. under N₂. The mixture was allowed to warm to r.t. and stirredfor 90 min. before pouring to water (2 mL). After stirring for 20 min.to the mixture was added NaHCO₃ to adjust pH to 7 and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated to give a residue, which was purified by a standard methodto give3-[4-isopropylamino-6-(pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenol.

¹H NMR (DMSO-d₆) δ: 11.12-11.05 (m, 1H), 9.72 (br.s., 1H), 8.67-8.60 (m,2H), 8.38-8.31 (m, 2H), 8.15-8.00 (m, 1H), 7.82-7.74 (m, 2H), 7.32 (t,J=8.2 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 4.433-4.17 (m, 1H), 1.26-1.22 (m,6H). LC-MS: m/z 323.2 (M+H)⁺.

Example 5 Preparation of Compounds of Formula I Wherein Ring A and RingB are Phenyl

The compounds of this Example are prepared by general Scheme 5, setforth below.

Example 5 Step 2 Preparation of4-chloro-N,6-diphenyl-1,3,5-triazin-2-amine

To a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (1 g, 4.4 mol) inacetone (10 mL) was added dropwise a solution of aniline (0.41 g, 4.4mol) in acetone (2 mL) at 0° C. via syringe under N₂. After theaddition, the mixture was stirred at 0° C. under N₂ for 4 hrs. Thereaction mixture was adjusted to pH 7 with saturated NaHCO₃. The cakewas dissolved in ethyl acetate (500 ml), dried over anhydrous Na₂SO₄,concentrated and purified via silica gel chromatography to give4-chloro-N,6-diphenyl-1,3,5-triazin-2-amine as a white solid.

¹H NMR (CDCl3) δ: 8.42 (d, J=7.6 Hz, 1H), 8.33 (d, J=7.6 Hz, 1H),7.57-7.43 (m, 3H), 5.57-5.49 (m, 1H), 4.42-4.24 (m, 1H), 1.31-1.23 (m,6H).

Example Step 3 Preparation of2,6-diphenyl-N⁴-(tetrahydrofuran-3-yl)-1,3,5-triazine-2,4-diaminetetrahydrofuran-3-amine Compound 203

To a solution of (4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-phenyl-amine(150 mg, 0.532 mmol) in anhydrous THF (5 mL) was added a solution of1-amino-2-methyl-propan-2-ol (71 mg, 0.796 mmol) in THF (2 mL) viasyringe at room temperature and the result mixture was stirred at roomtemperature for 16 hrs. The reaction was quenched by water (15 mL) andextracted with ethyl acetate. The organic layer was dried over Na₂SO₄,concentrated and purified by a standard method to give pure2-methyl-1-(4-phenyl-6-phenylamino-[1,3,5]triazin-2-yl-amino)-propan-2-ol.

¹H NMR (METHANOL-d₄) δ: 8.35 (t, J=9.6 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H),7.53-7.43 (m, 3H), 7.31 (t, J=5.5 Hz, 2H), 7.03 (t, J=7.6 Hz, 1H),3.56-3.47 (m, 2H), 1.26 (s, 6H). LC-MS: m/z 336.2 (M+H)⁺.

Other compounds were produced following Example 5, step 3 using theappropriate amine 6.

Compound 174N²,6-diphenyl-N⁴-(tetrahydrofuran-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.39 (br.s., 1H), 8.35 (d, J=6.9 Hz, 1H), 7.75(d, J=7.6 Hz, 3H), 7.52-7.43 (m, 3H), 7.31 (br.s., 2H), 7.02 (t, J=7.6Hz, 1H), 4.60 (br.s., 1H), 4.05-3.95 (m, 2H), 3.89-3.83 (m, 1H), 3.76(dd, J=8.9, 3.4 Hz, 1H), 2.34-2.29 (m, 1H), 2.04-1.97 (m, 1H). LC-MS:m/z 333.9 (M+H)⁺.

Compound 175 N²-(oxetan-3-yl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.35 (d, J=7.2 Hz, 2H), 7.71 (br.s., 2H),7.51-7.41 (m, 3H), 7.30 (br.s., 2H), 7.02 (t, J=7.2 Hz, 1H), 5.25-5.10(m, 1H), 4.93 (br.s., 2H), 4.69 (br.s., 2H). LC-MS: m/z 320.0 (M+H)⁺.

Compound 176N²-(3-methyloxetan-3-yl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.35 (d, J=7.6 Hz, 2H), 7.70 (br, 2H), 7.52-7.42(m, 3H), 7.31 (t, J=7.6 Hz, 2H), 7.06 (br.s., 1H), 4.88 (br.s., 2H),4.52-4.88 (br.s., 2H), 1.77 (s, 3H). LC-MS: m/z 334.0 (M+H)⁺.

Compound 225N²-(2-methoxyethyl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.42-8.34 (m, 2H), 7.75 (d, J=6.9 Hz, 2H),7.54-7.44 (m, 3H), 7.32 (t, J=7.6 Hz, 2H), 7.04 (t, J=7.1 Hz, 1H),3.7-3.58 (m, 4H), 3.41 (s, 3H). LC-MS: m/z 322.0 (M+H)⁺.

Compound 237N²-(oxetan-2-ylmethyl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.40-8.33 (m, 2H), 7.74 (d, J=8.2 Hz, 2H),7.52-7.43 (m, 3H), 7.31 (t, J=8.2 Hz, 2H), 7.02 (t, J=7.6 Hz, 1H),5.1-5.04 (m, 1H), 4.72-4.66 (m, 1H), 4.62-4.57 (m, 2H), 3.89-3.68 (m,2H), 2.71-2.67 (m, 1H), 2.61-2.52 (m, 1H). LC-MS: m/z 333.9 (M+H)⁺.

Compound 238 2-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)ethanol

¹H NMR (METHANOL-d₄) δ: 8.39-8.31 (m, 2H), 7.75 (d, J=7.6 Hz, 2H),7.52-7.43 (m, 3H), 7.31 (t, J=7.6 Hz, 2H), 7.02 (t, J=6.9 Hz, 1H), 3.76(t, J=5.5 Hz, 2H), 3.65-3.59 (m, 2H). LC-MS: m/z 308.0 (M+H)⁺.

Compound 2392,2-dimethyl-3-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)propan-1-ol

¹H NMR (METHANOL-d₄) δ: 8.35-8.29 (m, 2H), 7.74 (t, J=6.5 Hz, 2H),7.54-7.44 (m, 3H), 7.32 (q, J=7.6 Hz, 2H), 7.06-7.01 (m, 1H), 3.39 (d,J=9.5 Hz, 2H), 3.22 (s, 2H), 0.94 (s, 6H). LC-MS: m/z 350.1 (M+H)⁺.

Compound 2401-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ: 8.39-8.32 (m, 2H), 7.74 (d, J=7.8 Hz, 2H),7.52-7.43 (m, 3H), 7.31 (t, J=7.8 Hz, 2H), 7.02 (t, J=7.1 Hz, 1H),4.06-3.98 (m, 1H), 3.56-3.33 (m, 2H), 1.22 (d, J=6.4 Hz, 3H). LC-MS: m/z321.9 (M+H)⁺.

Compound 2412-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)propan-1-ol

¹H NMR (METHANOL-d₄) δ: 8.39-8.32 (m, 2H), 7.74 (d, J=7.6 Hz, 2H),7.52-7.42 (m, 3H), 7.30 (t, J=7.6 Hz, 2H), 7.02 (t, J=7.6 Hz, 1H),4.37-4.25 (m, 1H), 3.65-3.58 (m, 2H), 1.27 (d, J=6.9 Hz, 3H). LC-MS: m/z322.0 (M+H)⁺.

Compound 2423-methyl-2-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)butan-1-ol

¹H NMR (METHANOL-d₄) δ: 8.41-8.33 (m, 2H), 7.75 (d, J=8.0 Hz, 2H),7.52-7.44 (m, 3H), 7.31 (t, J=7.6 Hz, 2H), 7.03 (t, J=7.6 Hz, 1H),4.25-4.05 (m, 1H), 3.73 (d, J=4.8 Hz, 2H), 2.12-2.02 (m, 1H), 1.04-1.00(m, 3H). LC-MS: m/z 350.1 (M+H)⁺.

Compound 267(1R,3R)-3-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)cyclopentanol

¹H NMR (METHANOL-d₄) δ: 8.42-8.32 (m, 2H), 7.80-7.75 (m, 2H), 7.52-7.42(m, 3H), 7.33-7.29 (m, 2H), 7.01 (t, J=7.2 Hz, 1H), 4.63-4.58 (m, 1H),4.39-4.36 (m, 1H), 2.32-2.25 (m, 1H), 2.10-2.03 (m, 2H), 1.84-1.78 (m,1H), 1.69-1.52 (m, 2H). LC-MS: m/z 348.1 (M+H)⁺.

Compound 268N²,6-diphenyl-N⁴-(tetrahydro-2H-pyran-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.43-8.36 (m, 2H), 7.77 (t, J=7.6 Hz, 2H),7.55-7.45 (m, 3H), 7.34 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.2 Hz, 1H),4.26-4.05 (m, 2H), 3.86-3.83 (m, 1H), 3.55-3.50 (m, 1H), 3.40-3.33 (m,1H), 2.15-2.06 (m, 1H), 1.87-1.66 (m, 3H). LC-MS: m/z 348.1 (M+H)⁺.

Compound 269N²-(1-methoxypropan-2-yl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.41-8.35 (m, 2H), 7.78 (d, J=7.2 Hz, 2H),7.55-7.45 (m, 3H), 7.33 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.2 Hz, 1H),4.54-4.37 (m, 1H), 3.58-3.55 (m, 1H), 3.46-3.41 (m, 1H), 3.41 (s, 3H),1.30 (d, J=6.9 Hz, 3H). LC-MS: m/z 336.1 (M+H)⁺.

Compound 296N²-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-N⁴,6-diphenyl-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 9.60-9.47 (m, 1H), 8.36-8.30 (m, 2H), 7.89-7.84 (m,2H), 7.80-7.61 (m, 1H), 7.56-7.50 (m, 3H), 7.31 (t, J=7.6 Hz, 2H), 6.70(t, J=6.9 Hz, 1H), 4.30-4.15 (m, 1H), 2.32-2.25 (m, 1H), 2.07-1.90 (m,1H), 1.65-1.1 (m, 8H). LC-MS: m/z 358.1 (M+H)⁺.

Compound 352(1S,2R)-2-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)cyclopentanol

¹H NMR (METHANOL-d₄) δ: 8.42-8.32 (m, 2H), 7.77 (t, J=7.9 Hz, 2H),7.56-7.46 (m, 3H), 7.34 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.2 Hz, 1H),4.42-4.23 (m, 2H), 2.17-2.10 (m, 1H), 1.99-1.87 (m, 2H), 1.80-1.70 (m,3H). LC-MS: m/z 348.2 (M+H)⁺.

Compound 3623-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylamino)cyclohex-2-enone

¹H NMR (METHANOL-d₄) δ: 8.47 (d, J=7.6 Hz, 1H), 7.78 (br.s., 2H),7.60-7.50 (m, 3H), 7.39 (t, J=8.2 Hz, 2H), 7.23 (br.s., 1H), 7.12 (t,J=7.6 Hz, 1H), 2.75 (t, J=6.2 Hz, 2H), 2.43 (t, J=6.2 Hz, 2H), 2.12-2.03(m, 2H). LC-MS: m/z 358.2 (M+H)⁺.

Example 6 Preparation of Additional Compounds of Formula I Wherein RingA is Phenyl

The compounds of this Example are prepared by general Scheme 6, setforth below.

Example 6, Step 2 Preparation oftert-Butyl-(4-chloro-6-phenyl-[1,3,5]triazin-2-yl)-amine

To a solution of 2,4-dichloro-6-phenyl-1,3,5-triazine (500 mg, 2.212mmol) in anhydrous THF (4 mL) was added dropwise a solution oftert-butylamine (194.1 mg, 2.654 mol) in THF (1 mL) at room temperaturevia syringe under N₂. After the addition, the mixture was stirred atroom temperature under N₂ for 2 hrs. The reaction was quenched by water(5 mL) and extracted with ethyl acetate. The organic layer was dried,concentrated to afford tert-butyl-(4-chloro-6-phenyl-[1,3, and5]-triazin-2-yl)-amine as a white solid, which was used the directly inthe next step without purification.

Other amines 6 were also employed using the standard procedure describedabove to give the desired intermediates and were also used in the nextstep directly without further purification.

Example 6, Step 3 Preparation of Compound 2276-(2-fluorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

A mixture of tert-butyl-(4-chloro-6-phenyl-[1, 3, and5]triazin-2-yl)-amine (186.1 mg, 0.71 mmol), pyridine-4-amine (80 mg,0.85 mmol), CsF (107.85 mg, 0.71 mmol) and DIEA (275.30 mg, 2.13 mmol)in DMSO (4 mL) was heated to 80° C. for 2 hours. The mixture wasfiltered and purified by a standard method to give6-(2-fluorophenyl)-N²-isopropyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine.This compound was also produced by Step 3, procedure A of Example 4.

Additional compounds of one aspect of the invention are producedaccording to Scheme 6 and the methods set forth in this example usingthe appropriate amine 6 and the appropriate amine 4.

Compound 186N²-sec-butyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.44-8.33 (m, 4H), 7.92 (m, 2H), 7.54 (t, J=7.14Hz, 1H), 7.48 (t, J=7.14 Hz, 2H), 4.30-4.09 (m, 1H), 1.66 (m, 2H), 1.28(d, J=6.56 Hz, 3H), 1.02 (t, J=7.29 Hz, 3H). LC-MS: m/z 321.1 (M+H)⁺.

Compound 287N²-cyclopentyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 8.43-8.37 (m, 4H), 8.06-8.02 (m, 2H), 7.52-7.46 (m,3H), 4.52-4.36 (m, 1H), 2.08 (m, 2H), 1.80-1.62 (m, 6H). LC-MS: m/z333.1 (M+H)⁺.

Compound 188N²-cyclobutyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 8.50-8.30 (m, 4H), 8.00-7.90 (m, 2H), 7.60-7.40 (m,3H), 4.55 (m, 1H), 2.45 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H). LC-MS: m/z319.1 (M+H)⁺.

Compound 189N²-tert-butyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 8.50-8.30 (m, 4H), 8.00-7.90 (m, 2H), 7.60-7.40 (m,3H), 1.56 (m, 9H). LC-MS: m/z 321.1 (M+H)⁺.

Compound 190N²-isobutyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.35-8.21 (m, 4H), 7.84-7.78 (m, 2H), 7.48-7.34(m, 3H), 3.30 (d, J=2.0 Hz, 2H), 1.96-1.87 (m, 1H), 0.92 (d, J=6.8 Hz,6H). LC-MS: m/z 321.0 (M+H)⁺.

Compound 191N²-neopentyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.57-8.52 (m, 1H), 8.43-8.28 (m, 4H), 7.60-7.37(m, 3H), 3.36 (d, J=2.0 Hz, 2H), 0.94 (d, J=9.6 Hz, 9H). LC-MS: m/z335.1 (M+H)⁺.

Compound 211N²-butyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.37-8.25 (m, 4H), 7.84 (d, J=6.41 Hz, 2H), 7.46(t, J=7.12 Hz, 1H), 7.40 (t, J=7.12 Hz, 2H), 3.50-3.41 (m, 2H), 1.61 (m,2H), 1.40 (m, 2H), 0.93 (t, J=7.23 Hz, 3H). LC-MS: m/z 321.0 (M+H)⁺.

Compound 212N²-isopentyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.30-8.18 (m, 4H), 7.77 (d, J=5.98 Hz, 2H),7.41-7.31 (m, 3H), 3.45-3.36 (m, 2H), 1.60 (m, 1H), 1.45 (m, 2H), 0.86(d, J=6.52 Hz, 3H). LC-MS: m/z 335.1 (M+H)⁺.

Compound 213N²-(3-methylbutan-2-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.33-8.23 (m, 4H), 7.85-7.80 (m, 2H), 7.44 (t,J=7.03 Hz, 1H), 7.38 (t, J=7.03 Hz, 2H), 4.14-3.97 (m, 1H), 1.83 (m,1H), 1.14 (d, J=6.69 Hz, 3H), 0.94-0.90 (m, 6H). LC-MS: m/z 335.1(M+H)⁺.

Compound 2156-phenyl-N²-(pyridin-4-yl)-N⁴-(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.44 (m, 2H), 8.36 (m, 2H), 7.90 (m, 2H), 7.55(t, J=7.32 Hz, 1H), 7.48 (t, J=7.32 Hz, 2H), 4.35-4.20 (m, 2H). LC-MS:m/z 346.9 (M+H)⁺.

Compound 216N²-(cyclopropylmethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.43-8.32 (m, 4H), 7.91 (m, 2H), 7.53 (t, J=7.21Hz, 1H), 7.47 (t, J=7.21 Hz, 2H), 3.43-3.36 (m, 2H), 1.18 (m, 1H), 0.54(m, 2H), 0.32 (m, 2H). LC-MS: m/z 319.0 (M+H)⁺.

Compound 217N²-cyclopropyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.46-8.33 (m, 4H), 8.01-7.91 (m, 2H), 7.54-7.44(m, 3H), 2.88-2.99 (m, 1H), 0.87 (m, 2H), 0.64 (m, 2H). LC-MS: m/z 305.0(M+H)⁺.

Compound 218N²-(1-methylcyclopropyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.51-8.33 (m, 4H), 8.05-7.90 (m, 2H), 7.54-7.44(m, 3H), 1.54 (s, 3H), 0.91-0.77 (m, 4H). LC-MS: m/z 319.0 (M+H)⁺.

Compound 219N²-(2-methylcyclopropyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.57-8.40 (m, 4H), 7.98-8.09 (m, 2H), 7.59 (t,J=7.23 Hz, 1H), 7.53 (t, J=7.23 Hz, 2H), 2.66 (m, 1H), 1.29 (d, J=5.43Hz, 3H), 1.05 (m, 1H), 0.91 (m, 1H), 0.70 (m, 1H). LC-MS: m/z 319.2(M+H)⁺.

Compound 220N²-(2-methylbutyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.47 (m, 2H), 8.39 (d, J=5.80 Hz, 2H), 7.97 (m,2H), 7.59 (t, J=6.44 Hz, 1H), 7.53 (t, J=6.44 Hz, 2H), 3.58-3.29 (m,2H), 1.85 (m, 1H), 1.60 (m, 1H), 1.32 (m, 1H), 1.06-1.02 (m, 6H). LC-MS:m/z 335.2 (M+H)⁺.

Compound 221N²-((2-methyltetrahydrofuran-2-yl)methyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.51-8.41 (m, 4H), 7.99 (m, 2H), 7.61 (t, J=7.22Hz, 1H), 7.55 (t, J=7.22 Hz, 2H), 3.98 (m, 2H), 3.78-3.65 (m, 2H),2.10-1.80 (m, 4H), 1.36 (s, 3H). LC-MS: m/z 363.1 (M+H)⁺.

Compound 2226-phenyl-N²-(pyridin-4-yl)-N⁴-((tetrahydrofuran-2-yl)methyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.53-8.42 (m, 4H), 8.02 (m, 2H), 7.62 (t, J=7.21Hz, 1H), 7.56 (t, J=7.21 Hz, 2H), 4.27 (m, 1H), 4.01 (m, 1H), 3.86 (q,J=7.23 Hz, 1H), 3.75 (m, 1H), 3.68 (m, 1H), 2.17-1.83 (m, 4H). LC-MS:m/z 349.2 (M+H)⁺.

Compound 234N²-(morpholin-2-ylmethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.42 (d, J=7.2 Hz, 1H), 8.39-8.32 (m, 3H), 7.89(d, J=4.8 Hz, 2H), 7.51 (d, J=6.8 Hz, 1H), 7.48-7.44 (m, 2H), 3.90-3.87(m, 1H), 3.76-3.74 (m, 1H), 3.63-3.52 (m, 3H), 2.99-2.96 (m, 1H),2.81-2.78 (m, 2H), 2.62-2.53 (m, 1H). LC-MS: m/z 364.0 (M+H)⁺.

Compound 2356-phenyl-N²-(pyridin-4-yl)-N⁴-(tetrahydrofuran-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 9.8-10.0 (m, 1H), 8.1-8.4 (m, 4H), 7.9-8.1 (m, 1H),7.6-7.8 (m, 2H), 7.3-7.5 (m, 3H), 4.3-4.6 (m, 1H), 3.75-3.85 (m, 1H),3.7-3.75 (m, 1H), 3.55-3.65 (m, 1H), 3.45-3.55 (m, 1H), 2.0-2.15 (m,1H), δ1.75-1.85 (m, 1H). LC-MS: m/z 335.1 (M+H)⁺.

Compound 236N²-(oxetan-3-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.3-8.5 (m, 4H), 7.8-8.0 (m, 2H), 7.45-7.6 (m,3H), 5.15-5.4 (m, 1H), 5.03 (t, J=6.8 Hz, 2H), 4.76 (t, J=6.4 Hz, 2H).LC-MS: m/z 320.9 (M+H)⁺.

Compound 248N²-ethyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (CDCl3) δ: 8.50 (m, 2H), 8.43-8.32 (m, 2H), 7.65 (m, 2H),7.55-7.46 (m, 3H), 7.20-7.08 (m, 1H), 5.45-5.29 (m, 1H), 3.66-3.54 (m,2H), 1.32 (t, J=7.25 Hz, 3H). LC-MS: m/z 292.9 (M+H)⁺.

Compound 2496-phenyl-N²-propyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.46-8.35 (m, 4H), 7.96 (m, 2H), 7.55 (t, J=7.25Hz, 1H), 7.49 (t, J=7.25 Hz, 2H), 3.56-3.45 (m, 2H), 1.73 (m, 2H), 1.05(t, J=7.35 Hz, 3H). LC-MS: m/z 307.0 (M+H)⁺.

Compound 250N²-(cyclobutylmethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.29-8.48 (m, 4H), 7.88-7.95 (m, 2H), 7.49-7.51(m, 3H), 3.48-3.61 (m, 2H), 2.60-2.75 (m, 1H), 2.08-2.18 (m, 2H),1.75-2.00 (m, 4H). LC-MS: m/z 332.4 (M+H)⁺.

Compound 251N²-(3-methyloxetan-3-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.3-8.5 (m, 4H), 7.8-8.0 (m, 2H), 7.4-7.6 (m,3H), 4.96 (d, J=6.4 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 1.81 (s, 3H).LC-MS: m/z 334.9 (M+H)⁺.

Compound 252N²-(2-methoxy-2-methylpropyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.30-8.49 (m, 4H), 7.88-7.98 (m, 2H), 7.46-7.51(m, 3H), 3.62 (s, 1H), 3.70 (s, 2H), 3.30 (s, 3H), 1.25 (s, 6H). LC-MS:m/z 350.43 (M+H)⁺.

Compound 253N²-(3,3-difluorocyclobutyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.27-8.18 (m, 4H), 7.73 (m, 2H), 7.37 (t, J=6.92Hz, 1H), 7.31 (t, J=6.92 Hz, 2H), 4.34-4.26 (m, 1H), 2.89 (m, 2H), 2.53(m, 2H). LC-MS: m/z 354.9 (M+H)⁺.

Compound 254N²-(4,4-difluorocyclohexyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.47-8.35 (m, 4H), 7.93 (m, 2H), 7.56 (t, J=7.19Hz, 1H), 7.50 (t, J=7.19 Hz, 2H), 4.28-4.12 (m, 1H), 1.76-2.18 (m, 8H).LC-MS: m/z 383.1 (M+H)⁺.

Compound 255N²-(3,3-dimethylbutan-2-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.33-8.42 (m, 4H), 7.91-7.96 (m, 2H), 7.46-7.53(m, 3H), 1.36 (d, J=6.4 Hz, 1H), 1.21 (d, J=6.8 Hz, 2H), 1.01 (s, 9H).LC-MS: m/z 349.1 (M+H)⁺.

Compound 2564-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclohexanol

¹H NMR (METHANOL-d₄) δ: 8.56-8.30 (m, 4H), 7.90 (d, J=5.5 Hz, 2H),7.53-7.44 (m, 3H), 3.85-4.1 (m, 1H), 3.62 (s, 1H), 2.15 (s, 2H), 2.03(s, 2H), 1.46-1.35 (m, 4H). LC-MS: m/z 363.2 (M+H)⁺.

Compound 257N²-(1-cyclopropylethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.40-8.34 (m, 4H), 7.94-7.90 (d, J=16 Hz, 3H),7.53-7.45 (m, 3H), 4.59 (br.s., 1H), 3.75-3.68 (m, 1H), 1.36-1.35 (d,J=4 Hz, 1H), 1.05 (br.s., 1H), 0.59-0.47 (m, 3H), 0.3 (br.s., 1H).LC-MS: m/z 333.2 (M+H)⁺.

Compound 2586-phenyl-N²-(pyridin-4-yl)-N⁴-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 9.38 (m, 2H), 8.54 (m, 2H), 7.65-7.53 (m, 3H),7.03 (m, 2H), 4.39-4.30 (m, 1H), 4.05 (m, 2H), 3.64 (m, 2H), 2.06 (m,2H), 1.73 (m, 2H). LC-MS: m/z 349.2 (M+H)⁺.

Compound 2592,2-dimethyl-3-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-1-ol

¹H NMR (METHANOL-d4) δ: 9.38 (m, 2H), 8.54 (m, 2H), 7.65-7.53 (m, 3H),7.03 (m, 2H), 4.39-4.30 (m, 1H), 4.05 (m, 2H), 3.64 (m, 2H), 2.06 (m,2H), 1.73 (m, 2H). LC-MS: m/z 349.2 (M+H)⁺.

Compound 262N²-(2-ethoxyethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.46-8.35 (m, 4H), 7.93-7.91 (d, J=6 Hz, 2H),7.55-7.47 (m, 3H), 4.93-4.63 (m, 3H), 4.63 (br.s., 1H), 3.77-3.70 (m,4H), 3.62-3.57 (m, 2H), 1.23 (t, J=6.8 Hz, 3H). LC-MS: m/z 336.9 (M+H)⁺.

Compound 2636-phenyl-N²-(pyridin-4-yl)-N⁴-(3,3,3-trifluoropropyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.35-8.47 (m, 4H), 7.90-7.93 (m, 2H), 7.46-7.56(m, 3H), 3.75-3.82 (m, 2H), 2.57-2.65 (m, 2H). LC-MS: m/z 361.0 (M+H)⁺.

Compound 264N²-(oxetan-2-ylmethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (CDCl3) δ: 8.47 (d, J=5.41 Hz, 2H), 8.36 (m, 2H), 7.63 (m, 2H),7.52 (t, J=6.84 Hz, 1H), 7.46 (t, J=6.84 Hz, 2H), 7.18 (m, 1H),6.25-5.92 (m, 1H), 5.09 (m, 1H), 4.65 (m, 2H), 3.87-3.67 (m, 2H), 2.62(m, 2H). LC-MS: m/z 335.2 (M+H)⁺.

Compound 2652-methyl-1-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (CDCl3) δ: 8.51 (m, 2H), 8.36 (d, J=7.70 Hz, 2H), 7.65 (d, J=4.74Hz, 2H), 7.55 (t, J=7.70 Hz, 1H), 7.48 (t, J=7.70 Hz, 2H), 7.21 (m, 1H),5.86 (m, 1H), 3.59 (m, 2H), 1.33 (s, 6H). LC-MS: m/z 337.3 (M+H)⁺.

Compound 2711-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ: 9.38-9.44 (m, 2H), 8.54-8.59 (m, 2H), 7.55-7.64(m, 3H), 7.01-7.05 (m, 2H), 4.00-4.06 (m, 1H), 3.59-3.67 (m, 2H),1.29-1.30 (d, J=6.4 Hz, 3H). LC-MS: m/z 323.1 (M+H)⁺.

Compound 272N²-(1-methoxypropan-2-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.39-8.45 (m, 4H), 7.97-8.01 (m, 2H), 7.48-7.50(m, 3H), 4.35-4.62 (m, 1H), 3.57-3.61 (m, 2H), 3.43 (s, 3H), 1.32-1.33(d, J=4.0 Hz, 3H). LC-MS: m/z 337.1 (M+H)⁺.

Compound 2736-phenyl-N²-(pyridin-4-yl)-N⁴-(tetrahydro-2H-pyran-3-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 9.36-9.41 (m, 2H), 8.53-8.57 (m, 2H), 7.53-7.66(m, 3H), 7.01-7.05 (m, 2H), 4.17-4.39 (m, 1H), 4.02-4.11 (m, 1H),3.83-3.91 (m, 1H), 2.10-2.20 (m, 1H), 1.77-1.80 (m, 3H). LC-MS: m/z349.2 (M+H)⁺.

Compound 274N²-(2-methoxypropyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 9.29-9.33 (m, 2H), 8.48-8.52 (m, 2H), 7.52-7.61(m, 3H), 6.98-7.01 (m, 2H), 3.55-3.78 (m, 3H), 3.44 (s, 3H), 1.26-1.27(d, J=4.0 Hz, 3H). LC-MS: m/z 337.2 (M+H)⁺.

Compound 275N²-(3-methoxypropyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 8.36-8.41 (m, 4H), 7.93-7.95 (m, 2H), 7.49-7.51(m, 3H), 3.54-3.60 (m, 4H), 3.38 (s, 3H), 1.95-1.98 (m, 2H). LC-MS: m/z337.1 (M+H)⁺.

Compound 2763-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclobutanone

¹H NMR (METHANOL-d₄) δ: 8.39-8.44 (m, 4H), 7.97 (s, 2H), 7.48-7.56 (m,3H), 4.70-4.80 (m, 1H), 3.51-3.58 (m, 2H), 3.20-3.30 (m, 2H). LC-MS: m/z333.0 (M+H)⁺.

Compound 2782-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-1-ol

¹H NMR (METHANOL-d₄) δ: 9.28-9.33 (m, 2H), 8.46-8.51 (m, 2H), 7.49-7.54(m, 3H), 6.95-6.99 (m, 2H), 4.30-4.55 (m, 1H), 3.68-3.72 (m, 2H), 1.34(t, J=6.8 Hz, 1H). LC-MS: m/z 323.0 (M+H)⁺.

Compound 2793-methyl-2-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)butan-1-ol

¹H NMR (METHANOL-d₄) δ: 9.23-9.26 (m, 2H), 8.4 (d, J=8.0 Hz, 2H),7.41-7.5 (m, 3H), 6.89 (t, J=8.0 Hz, 2H), 4.1-4.3 (m, 1H), 3.6-3.8 (m,1H), 1.9-2.1 (m, 1H), 0.9-1.1 (m. 6H). LC-MS: m/z 351.1 (M+H)⁺.

Compound 280N²-cyclohexyl-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 9.34 (t, J=8.0 Hz, 2H), 8.51 (t, J=8.0 Hz, 2H),7.50-7.63 (m, 3H), 6.98-7.03 (m, 2H), 4.0-4.2 (m, 1H), 2.08 (t, J=12 Hz,2H), 1.85-1.87 (m, 2H), 1.52-1.53 (m, 1H), 1.28-1.51 (m, 5H). LC-MS: m/z347.1 (M+H)⁺.

Compound 2822-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclohexanol

¹H NMR (METHANOL-d4) δ: 9.18 (m 2H), 8.32 (m, 3H), 7.46-7.32 (m, 3H),6.82 (m, 2H), 4.13-4.02 (m, 1H), 3.96-3.90 (m, 1H), 1.71-1.30 (m, 8H).LC-MS: m/z 363.0 (M+H)⁺.

Compound 283(1S,3R)-3-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclopentanol

¹H NMR (DMSO-d6) δ: 9.37-9.22 (m, 2H), 9.18 (m, 2H), 8.88-8.69 (m, 1H),8.54-8.44 (m, 2H), 7.71-7.57 (m, 3H), 7.04 (d, J=7.85 Hz, 2H), 4.44 (m,1H), 4.18 (m, 1H), 2.33-1.54 (m, 6H). LC-MS: m/z 49.1 (M+H)⁺.

Compound 2841-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclobutanecarbonitrile

¹H NMR (METHANOL-d4) δ: 8.47 (m, 2H), 8.38 (m, 2H), 7.95 (m, 2H), 7.57(t, J=6.74 Hz, 1H), 7.50 (t, J=6.74 Hz, 2H), 2.88 (m, 2H), 2.57 (m, 2H),2.22 (m, 2H). LC-MS: m/z 344.0 (M+H)⁺.

Compound 2851-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclopropanecarbonitrile

¹H NMR (METHANOL-d4) δ: 9.46-9.35 (m, 2H), 8.71-8.55 (m, 2H), 7.70-7.54(m, 3H), 7.09-7.01 (m, 2H), 1.75 (m, 2H), 1.46 (m, 2H). LC-MS: m/z 330.0(M+H)⁺.

Compound 2863,3-dimethyl-2-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)butan-1-ol

¹H NMR (METHANOL-d4) δ: 9.43 (m, 2H), 8.59 (m, 2H), 7.67-7.55 (m, 3H),7.05 (m, 2H), 4.53-4.30 (m, 1H), 4.01 (m, 1H), 3.68 (m, 1H), 1.09 (s,9H). LC-MS: m/z 365.1 (M+H)⁺.

Compound 2912-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)butan-1-ol

¹H NMR (METHANOL-d4) δ: 9.38 (m, 2H), 8.54 (m, 2H), 7.65-7.51 (m, 3H),7.01 (m, 2H), 4.37-4.22 (m, 1H), 3.71 (m, 2H), 1.73 (m, 2H), 1.04 (m,3H). LC-MS: m/z 337.1 (M+H)⁺.

Compound 2942-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)ethanol

¹H NMR (METHANOL-d4) δ: 9.40 (m, 2H), 8.56 (m, 2H), 7.65-7.53 (m, 3H),7.03 (m, 2H), 3.84-3.72 (m, 4H). LC-MS: m/z 309.0 (M+H)⁺.

Compound 295N²-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 10.03 (br.s., 1H), 8.41-8.31 (m, 4H), 8.03-7.85 (m,3H), 7.59-7.52 (m, 3H), 4.30-4.10 (m, 1H), 2.33-2.09 (m, 1H), 2.05-1.90(m, 1H), 1.66-1.19 (m, 8H). LC-MS: m/z 359.2 (M+H)⁺.

Compound 297N²-(3-oxabicyclo[3.1.0]hexan-6-yl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ: 10.10 (br.s., 1H), 8.41-8.38 (m, 4H), 8.32-8.00 (m,1H), 7.95-7.85 (m, 2H), 7.58-7.53 (m, 3H), 3.97 (m, 2H), 3.73 (m, 2H),2.70-2.55 (m, 1H), 1.96 (m, 2H). LC-MS: m/z 347.0 (M+H)⁺.

Compound 300N²-(oxetan-3-ylmethyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ: 8.38-8.30 (m, 4H), 7.89 (m, 2H), 7.53-7.44 (m,3H), 4.83 (m, 2H), 4.56 (m, 2H), 3.83 (m, 2H), 3.35 (m, 1H). LC-MS: m/z335.0 (M+H)⁺.

Compound 3043-(4-phenyl-6-(pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)cyclohexanol

¹H NMR (METHANOL-d₄) δ: 8.33-8.44 (m, 4H), 7.90-7.93 (m, 2H), 7.46-7.54(m, 3H), 3.9-4.2 (m, 1H), 3.6-3.8 (m, 1H), 2.35-2.38 (m, 1H), 1.87-2.06(m, 3H), 1.26-1.36 (m, 4H). LC-MS: m/z 363.2 (M+H)⁺.

Compound 305N²-(3-methoxycyclobutyl)-6-phenyl-N⁴-(pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ: 9.32-9.38 (m, 2H), 8.49-8.54 (m, 2H), 7.49-7.62(m, 3H), 6.98-7.01 (m, 2H), 4.2-4.6 (m, 1H), 3.7-4.1 (m, 1H), 3.3 (br.s., 1H), 2.83-2.84 (m, 1H), 2.47-2.50 (m, 1H), 2.36-2.38 (m, 1H),2.0-2.04 (m, 1H). LC-MS: m/z 349.2 (M+H)⁺.

Example 7 Preparation of Compounds of Formula I Wherein R¹ and R³ areTaken Together with the Carbon Atom to which they are Attached to FormC(═O)

The compounds of this Example are prepared by general Scheme 7,Procedure 1 or 2, as set forth below.

Example 7, Step 3 (Procedure 1) Preparation ofN²,6-diphenyl-1,3,5-triazine-2,4-diamine

A mixture of 4-chloro-N,6-diphenyl-1,3,5-triazin-2-amine (4.0 g, 0.14mol) and NH₃.H₂O (40 mL) in THF (12 mL) was added in a sealed tube. Thereaction mixture was stirred at 80° C. for 16 hours. The mixture wasextracted with ethyl acetate (50 mL×3). The organic layer was dried overanhydrous Na₂SO₄ and concentrated to giveN²,6-diphenyl-1,3,5-triazine-2,4-diamine as a white solid, which wasused in the next step directly without further purification.

Preparation of Compound 179 Isobutyl4-phenyl-6-(phenyl-amino)-1,3,5-triazin-2-ylcarbamate (Procedure 1, Step4, reagent 17)

Pyridine (60 mg, 0.76 mmol) was added dropwise to a solution ofN²,6-diphenyl-1,3,5-triazine-2,4-diamine (100 mg, 0.38 mmol) in DCM (4mL) under ice-bath cooling. The mixture was then stirred 0° C. for 15min, then isobutyl carbonochloridate (63 mg, 0.46 mmol) was addeddropwise and the resultant mixture was stirred at rt for 1 hours. Thereaction mixture was concentrated and purified by a standard method togive isobutyl 4-phenyl-6-(phenyl-amino)-1,3,5-triazin-2-ylcarbamate.

¹H NMR (METHANOL-d₄) δ: 8.48 (d, J=7.2 Hz, 2H), 7.82 (br.s., 2H),7.55-7.46 (m, 3H), 7.36 (br.s., 2H), 7.07 (br.s., 1H), 4.01 (d, J=6.8Hz, 2H), 2.06-2.00 (m, 1H), 1.01 (d, J=6.8 Hz, 6H). LC-MS: m/z 364.0(M+H)⁺

Other compounds of one aspect of the invention were similarly preparedusing Example 7, Procedure 1, step 4 of this example and the appropriatechloridate 17.

Compound 160 isopropyl4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate

¹H NMR (DMSO-d₆) δ: 10.48 (br.s., 1H), 10.12 (br.s., 1H), 8.38 (d, J=7.2Hz, 2H), 8.02 (br.s., 2H), 7.61-7.53 (m, 3H), 7.33 (br.s., 2H), 7.04 (t,J=7.2 Hz, 1H), 4.98 (t, J=6.4 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H). LC-MS:m/z 350.1 (M+H)⁺

Compound 183 N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)pivalamide

¹H NMR (DMSO-d₆) δ: 10.14 (br.s., 1H), 9.95 (br.s., 1H), 8.40 (d, J=6.4Hz, 2H), 8.02 (br.s., 2H), 7.60-7.55 (m, 3H), 7.33 (br.s., 2H), 7.03(br.s., 1H), 1.27 (s, 9H). LC-MS: m/z 348.0 (M+H)⁺

Compound 208 Neopentyl4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate

¹H NMR (DMSO-d₆) δ: 10.57 (br.s., 1H), 10.12 (br.s., 1H), 8.38 (d, J=7.2Hz, 2H), 8.02 (br.s., 2H), 7.62-7.52 (m, 3H), 7.32 (t, J=7.2 Hz, 2H),7.03 (t, J=7.2 Hz, 1H), 3.85 (s, 2H), 0.96 (s, 9H). LC-MS: m/z 378.0(M+H)⁺

Compound 232 cyclopropylmethyl4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate

¹H NMR (DMSO-d₆) δ: 10.46. (br.s., 1H), 10.12 (br.s., 1H), 8.38 (d,J=7.2 Hz, 2H), 8.02 (br.s., 2H), 7.70-7.54 (m, 3H), 7.31 (br.s., 2H),7.02 (br.s., 1H), 4.00 (d, J=7.2 Hz, 2H), 0.88-0.85 (m, 1H), 0.56 (d,J=7.2 Hz, 2H), 0.35 (d, J=7.2 Hz, 2H). LC-MS: m/z 362.0 (M+H)⁺

Compound 233N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)cyclopropanecarboxamide

¹H NMR (DMSO-d₆) δ: 10.89. (br.s., 1H), 10.13 (br.s., 1H), 8.37 (d,J=7.2 Hz, 2H), 7.97 (br.s., 2H), 7.62-7.53 (m, 3H), 7.32 (br.s., 2H),7.04 (t, J=6.8 Hz, 1H), 2.32 (br.s., 1H), 0.90-0.84 (m., 4H). LC-MS: m/z332.1 (M+H)⁺

Compound 347N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)-1H-pyrazole-5-carboxamide

¹H NMR (METHANOL-d₄) δ: 8.37 (d, J=7.2 Hz, 2H), 7.75 (br.s., 2H), 7.72(s, 1H), 7.51-7.42 (m, 3H), 7.31 (t, J=7.6 Hz, 2H), 7.03 (t, J=7.2 Hz,1H), 6.89 (s, 1H). LC-MS: m/z 358.1 (M+H)⁺

Compound 4121-hydroxy-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)cyclopropanecarboxamide

¹H NMR (METHANOL-d₄) δ: 8.36 (d, J=7.2 Hz, 2H), 7.60-7.89 (m, 2H),7.48-7.39 (m, 3H), 7.29 (br.s., 2H), 7.25 (br.s., 2H), 1.29 (q, J=4.8Hz, 2H), 1.06 (q, J=4.4 Hz, 2H). LC-MS: m/z 347.9 (M+H)⁺

Compound 4135-oxo-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)pyrrolidine-2-carboxamide

H NMR (METHANOL-d₄) δ: 8.33 (d, J=7.6 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H),7.53-7.43 (m, 3H), 7.31 (t, J=7.6 Hz, 2H), 7.03 (t, J=6.9 Hz, 1H),4.12-4.08 (m, 1H), 2.44-2.25 (m, 3H), 2.18-2.10 (m, 1H). LC-MS: m/z375.2 (M+H)⁺

Compound 415N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)tetrahydrofuran-3-carboxamide

¹H NMR (METHANOL-d₄) δ: 8.24 (d, J=7.6 Hz, 2H), 7.55-7.37 (m, 6H), 7.25(d, J=7.2 Hz, 2H), 4.13-4.06 (m, 3H), 3.96 (q, J=8.0 Hz, 1H), 3.36 (q,J=7.26 Hz, 1H), 2.40-2.20 (m, 2H). LC-MS: m/z 362.2 (M+H)⁺

Preparation of Compound 414 1H-Pyrrole-2-carboxylic acid(4-phenyl-6-phenylamino-[1,3,5]triazin-2-yl)-amide (Procedure 1, step 4reagent 18)

To a solution of (4-amino-6-phenyl-[1,3,5]-triazin-2-yl)-phenyl-amine(210.6 mg, 0.8 mmol) in DCE (4 mL) was added Me₃Al (1 mL, 2.0 mmol) at0° C. The mixture was stirred for 50 mins, warmed up to room temperatureand 1H-Pyrrole-2-carboxylic acid methyl ester (50 mg, 0.4 mmol) wasadded. The mixture was stirred for 48 hr at 80° C. The reaction mixturewas diluted with H₂O (5 mL) and extracted with EtOAc (5 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated to givea crude residue, which was purified by a standard method to give1H-pyrrole-2-carboxylic acid(4-phenyl-6-phenyl-amino-[1,3,5]triazin-2-yl)-amide.

¹H NMR (METHANOL-d₄) δ: 8.39 (d, J=7.2 Hz, 1H), 7.75 (br.s., 2H),7.48-7.40 (m, 3H), 7.29 (t, J=7.2 Hz, 2H), 7.07 (d, J=2.8 Hz, 1H), 6.99(s, 2H), 6.18 (t, J=3.6 Hz, 1H). LC-MS: m/z 357.0 (M+H)⁺

Other compounds of one aspect of the invention were similarly preparedusing Example 7, Procedure 1, step 4 of this example, trimethylaluminum,and the appropriate ester 18.

2-oxo-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)propanamide

¹H NMR (DMSO-d₆) δ: 11.30 (s, 1H), 10.34 (s, 1H), 8.24 (d, J=6.4 Hz,2H), 7.82 (d, J=8.4 Hz, 2H), 7.65-7.50 (m, 3H), 7.38 (br.s., 2H), 7.11(t, J=7.2 Hz, 1H), 2.39 (br.s., 3H). LC-MS: m/z 334.2 (M+H)⁺.

Preparation of Compound 416 Tert-butyl4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate Example 7,(Procedure 2)

A mixture of 4-chloro-N,6-diphenyl-1,3,5-triazin-2-amine (141 mg, 0.5mmol), tert-butyl carbamate (69.6 mg, 0.6 mmol), Pd(AcO)₂ (24 mg, 0.05mmol), X-phos (67.3 mg, 0.1 mmol) and Cs₂CO₃ (326 mg, 1 mmol) in dioxane(5 mL) was purged with N₂ for 5 minutes. Then the mixture was heated to80° C. for 2 hours. The reaction mixture was filtered. The filtrate wasconcentrated and purified by a standard method to give tert-butyl4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate.

¹H NMR (DMSO-d₆) δ: 10.24. (br.s., 1H), 10.07 (br.s., 1H), 8.38 (d,J=6.8 Hz, 2H), 7.99 (br.s., 2H), 7.62-7.53 (m, 3H), 7.31 (br.s., 2H),7.04 (t, J=6.8 Hz, 1H), 1.51 (s, 9H). LC-MS: m/z 364.2 (M+H)⁺.

Other compounds of one aspect of the invention were similarly preparedusing Example 7, Procedure 2 of this example and the appropriate amine19.

Compound 181 ethyl 4-phenyl-6-(phenylamino)-1,3,5-triazin-2-ylcarbamate

¹H NMR (DMSO-d₆) δ: 10.58. (br.s., 1H), 10.12 (br.s., 1H), 8.37 (d,J=6.8 Hz, 2H), 8.05. (br.s., 2H), 7.60-7.52 (m, 3H), 7.32 (br.s., 2H),7.04 (t, J=7.6 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 1.27 (t, J=6.8 Hz, 1H).LC-MS: m/z 336.2 (M+H)⁺.

Compound 1821,1-dimethyl-3-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)urea

¹H NMR (DMSO-d₆) δ: 9.59. (br.s., 1H), 9.35 (br s., 1H), 8.34 (d, J=7.2Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.58-7.51 (m, 3H), 7.31 (t, J=7.2 Hz,2H), 7.02 (t, J=7.2 Hz, 1H), 2.97 (s, 6H). LC-MS: m/z 335.0 (M+H)⁺

Compound 207 1-ethyl-3-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)urea

¹H NMR (DMSO-d₆) δ: 10.10. (br.s., 1H), 9.84 (br.s., 1H), 8.30 (d, J=6.9Hz, 2H), 7.73 (br.s., 2H), 7.63-7.53 (m, 3H), 7.38 (br.s., 2H), 7.11 (t,J=7.2 Hz, 1H), 3.33 (br.s., 2H), 1.11 (br.s., 3H). LC-MS: m/z 335.2(M+H)⁺

Compound 209 N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)propionamide

¹H NMR (DMSO-d₆) δ: 10.53. (br.s., 1H), 10.10 (br.s., 1H), 8.36 (d,J=6.9 Hz, 2H), 7.96 (br.s., 2H), 7.62-7.53 (m, 3H), 7.33 (t, J=7.2 Hz,2H), 7.04 (t, J=7.2 Hz, 1H), 2.66-2.62 (m, 2H), 1.08 (t, J=7.6 Hz, 3H).LC-MS: m/z 320.2 (M+H)⁺

Compound 243N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)tetrahydrofuran-2-carboxamide

¹H NMR (DMSO-d₆) δ: 10.21. (br.s., 2H), 8.38 (d, J=7.6 Hz, 2H), 8.00(br.s., 2H), 7.63-7.53 (m, 3H), 7.34 (br.s., 2H), 7.06 (t, J=7.2 Hz,1H), 4.69 (br.s., 1H), 3.95-3.82 (m., 1H), 4.01-3.97 (m., 1H), 2.32-2.19(m., 1H), 2.03-1.85 (m., 3H). LC-MS: m/z 362.0 (M+H)⁺

Compound 2442-isopropoxy-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)acetamide

¹H NMR (DMSO-d₆) δ: 10.35. (br.s., 1H), 10.20 (br.s., 1H), 8.37 (d,J=7.2 Hz, 2H), 7.92 (br.s., 2H), 7.62-7.54 (m, 3H), 7.35 (br.s., 2H),7.08 (t, J=7.2 Hz, 1H), 4.37 (s, 2H), 3.70-3.67 (m., 1H), 1.15 (d, J=6.0Hz, 6H). LC-MS: m/z 364.0 (M+H)⁺

Compound 3242-hydroxy-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)propanamide

¹H NMR (DMSO-d₆) δ: 10.28. (br.s., 1H), 10.05. (br.s., 1H), 8.39 (d,J=7.2 Hz, 2H), 8.09 (br.s., 2H), 7.63-7.55 (m, 3H), 7.36 (br.s., 2H),7.05 (br.s., 1H), 5.88 (br.s., 1H), 4.38-4.35 (m, 1H), 1.35 (d, J=6.8Hz, 3H). LC-MS: m/z 335.9 (M+H)⁺

Compound 3482-hydroxy-N-(4-phenyl-6-(phenylamino)-1,3,5-triazin-2-yl)acetamide

¹H NMR (METHANOL-d₄) δ: 8.44 (d, J=7.6 Hz, 2H), 7.74 (br.s., 2H),7.60-7.49 (m, 3H), 7.38 (t, J=7.6 Hz, 2H), 7.12 (t, J=7.6 Hz, 1H), 4.94(s, 2H). LC-MS: m/z 322.1 (M+H)⁺

Additional compounds of Formula I that were prepared according toExample 1, step 3, Procedure C using the appropriate reagent 4 are asfollows:

Compound 450 methyl4-((4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-yl)amino)picolinate

¹H NMR (METHANOL-d₄) δ 9.08-8.74 (d, 1H), 8.49-8.43 (m, 3H), 8.13-7.83(m, 1H), 7.56-7.48 (m, 3H), 4.37-4.34 (m, 1H), 4.02 (s, 3H0, 1.35-1.30(m, 6H). LC-MS: m/z 365.2 (M+H)⁺

Compound 4512-(4-((4-(isopropylamino)-6-phenyl-1,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.48-8.23 (m, 4H), 7.72-7.63 (m, 1H), 7.56-7.44(m, 3H), 4.48-4.28 (m, 1H), 1.57 (s, 6H), 1.30 (d, 6H). LC-MS: m/z 365.2(M+H)⁺

Compound 452N2-isopropyl-N4-(4-(methylsulfonyl)phenyl)-6-phenyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.41-8.31 (m, 2H), 7.91-7.88 (m, 4H), 7.63-7.45(m, 4H), 5.51-5.08 (m, 1H), 4.48-4.19 (m, 1H), 3.05 (s, 3H), 1.30 (d,6H). LC-MS: m/z 384.2 (M+H)⁺

Additional compounds of Formula I were prepared according to Scheme 2using the appropriate reagents are as follows:

Compound 4536-(3,6-Difluoro-pyridin-2-yl)-N-isopropyl-N′-(3-methanesulfonyl-phenyl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.90-8.40 (m, 1H), 8.13-8.11 (m, 1H), 7.82-7.80(m, 2H), 7.71-7.67 (m, 1H), 7.59-7.57 (m, 1H), 4.42 (m, 1H), 3.16 (s,1H), 1.37-1.36 (d, J=6.8 Hz, 6H). LC-MS: m/z 421.2 (M+H)⁺.

Compound 455N-(3,5-Difluoro-phenyl)-N′-isopropyl-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.39-10.42 (m, 1H), 9.36-9.38 (m, 1H), 8.19-8.34 (m,2H), 7.68-7.71 (m, 2H), 6.79-6.84 (m, 1H), 4.10-4.15 (m, 1H), 1.18-1.23(m, 6H). LC-MS: m/z 412.3 (M+H)⁺.

Compound 456N-(5-Fluoro-pyridin-3-yl)-6-(3-fluoro-pyridin-2-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.70 (s, 1H), 8.61-8.40 (m, 1H), 8.15-8.10 (m,2H), 7.87-7.83 (m, 1H), 7.71-7.67 (m, 1H), 4.31-4.27 (m, 1H), 1.35-1.27(m, 6H). LC-MS: m/z 344.2 (M+H)⁺.

Compound 4586-(4-Amino-pyrimidin-2-yl)-N-(3,5-difluoro-phenyl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ (s, 1H), 7.50-7.52 (d, J=8.8 Hz, 2H), 6.58-6.67(m, 2H), 4.23-4.55 (m, 1H), 1.25-1.34 (m, 6H). LC-MS: m/z 359.0 (M+H)⁺.

Compound 459N-(3,5-Difluoro-phenyl)-6-(3-fluoro-pyridin-2-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.54-8.53 (d, 1H), 7.82-7.78 (m, 1H), 7.66-7.61(m, 1H), 7.55-7.50 (m, 2H), 6.60-6.53 (m, 1H), 4.39-4.24 (m, 1H),1.34-1.23 (m, 6H). LC-MS: m/z 361.2 (M+H)⁺.

Compound 460N-(3,5-Difluoro-phenyl)-6-(3,6-difluoro-pyridin-2-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.03-7.97 (m, 1H), 7.51-7.49 (m, 2H), 7.41-7.30(m, 1H), 6.68-6.64 (m, 1H), 4.31-4.24 (m, 1H), 1.35-1.27 (m, 6H). LC-MS:m/z 379.1 (M+H)⁺.

Compound 461N-(3,5-Difluoro-phenyl)-6-(3-fluoro-6-methoxy-pyridin-2-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.83-7.79 (m, 1H), 7.54-7.51 (m, 2H), 7.22-7.19(m, 1H), 6.78 (m, 1H), 4.35-4.31 (m, 1H), 4.08 (s, 3H), 1.39-1.31 (m,6H). LC-MS: m/z 391.3 (M+H)⁺.

Compound 4626-(6-Amino-pyridin-2-yl)-N-(6-fluoro-pyridin-3-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.65-8.58 (m, 1H), 8.50-8.30 (m, 1H), 8.20-7.61(m, 2H), 7.20-6.90 (m, 2H), 4.60-4.20 (m, 1H), 1.30 (d, 6H). LC-MS: m/z340.9 (M+H)⁺.

Compound 463N-(3,5-Difluoro-phenyl)-N′-isopropyl-6-(6-prop-1-ynyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.39-8.34 (m, 1H), 7.94-7.90 (t, 1H), 7.60-7.52(m, 3H), 6.62-6.57 (m, 1H), 4.50-4.24 (m, 1H), 2.12 (s, 3H), 1.34-1.29(m, 6H). LC-MS: m/z 380.9 (M+H)⁺.

Compound 464N-(3,5-Difluoro-phenyl)-N′-isopropyl-6-(6-methylamino-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.72-7.67 (m, 1H), 7.63-7.52 (m, 3H), 6.68-6.65(d, 1H), 6.60-6.56 (m, 1H), 4.36-4.16 (m, 2H), 2.98 (s, 3H). LC-MS: m/z441.9 (M+H)⁺.

Compound 465N-(3,5-Difluoro-phenyl)-6-(6-methylamino-pyridin-2-yl)-N′-(2,2,2-trifluoro-ethyl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ 8.00-7.85 (m, 1H), 7.84-7.78 (m, 1H), 7.50-7.45(m, 1H), 7.19-7.17 (m, 1H), 6.68-6.60 (m, 1H), 4.26-4.23 (m, 1H),3.14-3.12 (d, 3H), 1.33-1.28 (m, 6H). LC-MS: m/z 372.3 (M+H)⁺.

Compound 4666-(2,6-difluorophenyl)-N2-isopropyl-N4-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 9.0-8.4 (m, 1.0H), 8.05-7.75 (m, 1H), 7.75-7.4(m, 3H), 7.15-7.05 (m, 2H), 4.45-4.1 (m, 1H), 3.15 (s, 3H), 1.3 (d,J=6.4, 6H). LC-MS: m/z 419.8 (M+H)⁺.

Compound 467N-(3-Fluoro-phenyl)-N′-isopropyl-6-(6-prop-1-ynyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.33-8.31 (m, 1H), 7.92-7.82 (m, 2H), 7.58-7.56(m, 1H), 7.40-7.30 (m, 2H), 6.78-6.76 (m, 1H), 4.25-4.22 (m, 1H), 2.10(s, 3H), 1.33-1.28 (m, 6H). LC-MS: m/z 363.2 (M+H)⁺.

Compound 4686-(6-Amino-pyridin-2-yl)-N-isopropyl-N′-(5-trifluoromethyl-pyridin-3-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.21 (s, 2H), 8.48 (s, 1H), 7.70-7.58 (m, 2H),6.74-6.72 (m, 1H), 4.22 (m, 1H), 1.31-1.29 (d, J=8.0 Hz, 6H). LC-MS: m/z391.3 (M+H)⁺.

Compound 4696-[4-(3,5-Difluoro-phenylamino)-6-isopropylamino-[1,3,5]triazin-2-yl]-5-fluoro-pyridin-2-ol

¹H NMR (METHANOL-d₄) δ 7.71-7.65 (m, 2H), 7.49-7.47 (m, 2H), 6.77-6.72(m, 1H), 6.55-6.53 (m, 1H), 4.40-4.18 (m, 1H), 1.30-1.25 (m, 6H). LC-MS:m/z 377.2 (M+H)⁺.

Compound 4706-(6-Amino-pyridin-2-yl)-N-(5-fluoro-pyridin-3-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.38-9.35 (m, 1H), 8.77-8.63 (m, 2H), 8.09-7.86(m, 2H), 7.25-7.22 (m, 1H), 4.28-4.25 (m, 1H), 1.34 (dd, 6H). LC-MS: m/z341.1 (M+H)⁺.

Compound 471N-(3-Fluoro-phenyl)-N′-isopropyl-6-(2-methyl-oxazol-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.46-8.43 (m, 1H), 7.85-7.82 (m, 1H), 7.40-7.27(m, 2H), 6.78-6.74 (m, 1H), 4.25-4.22 (m, 1H), 2.57 (s, H), 1.29 (dd,J=13.2 Hz, 6.4 Hz, 6H). LC-MS: m/z 329.2 (M+H)⁺.

Compound 472N-(3-Fluoro-phenyl)-N′-isopropyl-6-(5-methyl-isoxazol-3-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.87-7.82 (m, 1H), 7.41-7.38 (m, 1H), 7.34-7.26(m, 1H), 6.77-6.68 (m, 2H), 4.38-4.21 (m, 1H), 2.53 (s, H), 1.29 (dd,J=10.8 Hz, 6.8 Hz, 6H). LC-MS: m/z 329.3 (M+H)⁺.

Compound 4736-(2,6-Difluoro-phenyl)-N-(3-fluoro-phenyl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 6.98-6.97 (m, 1H), 6.69-6.54 (m, 3H), 6.28-6.23(m, 2H), 5.92 (m, 1H), 3.47-3.44 (m, 1H), 0.49 (d, 6H). LC-MS: m/z 359(M+H)⁺.

Compound 4746-(2,6-Difluoro-phenyl)-N-(5-fluoro-pyridin-3-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.23-9.01 (m, 1H), 8.78-8.43 (m, 2H), 7.63-7.61(m, 1H), 7.20-7.16 (m, 2H), 4.31-4.20 (m, 1H), 1.33 (d, 6H). LC-MS: m/z361.1 (M+H)⁺.

Compound 475N-(3-Fluoro-phenyl)-N′-isopropyl-6-(4-trifluoromethyl-thiazol-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 8.00-7.86(m, 1H), 7.52-7.50 (m, 1H), 7.36-7.27 (m, 1H), 4.25-4.08 (m, 1H), 1.21(d, J=6.4 Hz, 6H). LC-MS: m/z 399.0 (M+H)⁺.

Compound 476N-(3,5-Difluoro-phenyl)-N′-isopropyl-6-(2-methyl-oxazol-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67 (br, 1H), 7.42 (d, J=9.2 Hz, 2H), 6.77-6.72(m, 1H), 4.28-4.23 (m, 1H), 2.56 (s, 3H), 1.28 (d, J=9.6 Hz, 6H). LC-MS:m/z 347.1 (M+H)⁺.

Compound 4776-(6-amino-3-fluoropyridin-2-yl)-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.55-7.45 (m, 2H), 7.45-7.35 (m, 1H), 7.0-6.9 (m,1H), 6.65-6.5 (m, 1H), 4.4-4.15 (m, 1H), 1.4-1.25 (m, 6H). LC-MS: m/z376.2 (M+H)⁺.

Compound 4786-(4-Amino-pyrimidin-2-yl)-N-cyclopropylmethyl-N′-(3,5-difluoro-phenyl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.26-8.25 (d, J=5.6 Hz, 1H), 7.532-7.490 (m, 2H),6.66-6.57 (m, 2H), 3.43-3.23 (m, 2H), 1.16-1.18 (m, 1H), 0.58-0.51 (m,2H), 0.34-0.29 (m, 2H). LC-MS: m/z 371.2 (M+H)⁺.

Compound 4796-(4-Amino-pyrimidin-2-yl)-N-tert-butyl-N′-(3,5-difluoro-phenyl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.28-8.26 (d, J=5.2 Hz, 1H), 7.49-7.47 (d, J=8Hz, 2H), 6.66-6.60 (m, 2H), 1.54 (s, 9H). LC-MS: m/z 373.2 (M+H)⁺.

Compound 4806-(4-Amino-pyrimidin-2-yl)-N-(3,5-difluoro-phenyl)-N′-(2,2,2-trifluoro-ethyl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.29-8.26 (m, 1H), 7.55-7.44 (m, 2H), 6.67-6.59(m, 2H), 4.44-4.20 (m, 2H). LC-MS: m/z 399.2 (M+H)⁺.

Compound 4816-(4-amino-6-(trifluoromethyl)pyrimidin-2-yl)-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.53 (d, J=8.0 Hz, 2H), 6.98 (s, 1H), 6.63-6.55(m, 1H), 4.50-4.23 (m, 1H), 1.34 (d, J=6.2 Hz, 6H). LC-MS: m/z 427.1(M+H)⁺.

Compound 4826-(2-Amino-pyrimidin-4-yl)-N-(3,5-difluoro-phenyl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ 8.47-8.46 (m, 1H), 7.60-7.48 (m, 3H), 4.26-4.22(m, 1H), 1.33-1.26 (m, 6H). LC-MS: m/z 372.3 (M+H)⁺.

Compound 4836-(4,6-dichloropyridin-2-yl)-N2-isopropyl-N4-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d6) δ 10.40 (br, 1H), 8.88 (s, 1H), 8.34-8.18 (m, 2H), 7.99(s, 1H), 7.81-7.79 (m, 1H), 7.56-7.53 (m, 2H), 4.23 (br, 1H), 3.18 (m,3H), 1.20 (s, 6H). LC-MS: m/z 475.0 (M+H)⁺.

Compound 4846-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-N2-isopropyl-N4-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ 8.52 (s, 1H), 8.03-7.95 (m, 2H), 7.79 (br, 1H),7.61-7.53 (m, 2H), 4.36-4.28 (m, 1H), 3.11 (d, 3H), 1.31-1.21 (m, 6H).LC-MS: m/z 471.1 (M+H)⁺.

Compound 4856-(6-amino-4-chloropyridin-2-yl)-N²-(3,5-difluorophenyl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 7.66 (s, 1H), 7.49-7.47 (d, 2H), 6.73 (s, 1H),6.57-6.50 (m, 1H), 4.47-4.09 (m, 1H), 1.35-1.26 (m, 6H). LC-MS: m/z392.1 (M+H)⁺.

Compound 4866-(4-chloro-6-methoxypyridin-2-yl)-N²-(3,5-difluorophenyl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.05 (s, 1H), 7.52 (br, 2H), 7.00 (s, 1H),6.58-6.52 (m, 1H), 4.40-4.21 (m, 1H), 4.07 (s, 3H), 1.31-1.29 (d, 6H).LC-MS: m/z 407.1 (M+H)⁺.

Compound 487(2-(4-((3,5-difluorophenyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-6-(trifluoromethyl)pyridin-4-yl)methanol

¹H NMR (METHANOL-d₄) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.54-7.52 (d, J=8 Hz,2H), 6.60-6.54 (m, 1H), 4.83 (s, 2H), 4.47-4.22 (m, 1H), 1.33-1.31 (d,J=6.4 Hz, 6H). LC-MS: m/z 441.1 (M+H)⁺.

Compound 4886-(6-(1,1-difluoroethyl)-4-fluoropyridin-2-yl)-N²-isopropyl-N⁴-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.95 (m, 1H), 8.3 (m, 1H), 7.75 (m, 1H), 7.6-7.5(m, 3H), 4.4 (m, 1H), 3.15 (s, 3H), 2.2-2.0 (m, 3H), 1.4-1.3 (m, 6H).

Compound 4896-(6-amino-4-fluoropyridin-2-yl)-N²-(3,5-difluorophenyl)-N⁴-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO) δ 10.15 (m, 1H), 8.0 (m, 1H), 7.7-7.5 (m, 2H), 7.2 (m,1H), 6.75 (m, 1H) 6.36 (m, 1H), 6.26 (m, 2H), 4.4-4.0 (m, 1H), 1.2 (m,6H).

Compound 490(2-chloro-6-(4-((3,5-difluorophenyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)pyridin-4-yl)methanol

¹H NMR (METHANOL-d₄) δ 10.28-10.24 (m, 1H), 8.29 (s, 1H), 8.16-7.88 (m,1H), 7.71-7.54 (m, 2H), 7.54-7.53 (d, 1H), 6.80-6.72 (m, 1H), 5.63-5.60(q, 2H), 4.63-4.61 (m, 1H), 4.33-4.05 (m, 1H), 1.21-1.19 (d, 6H). LC-MS:m/z 407.1 (M+H)⁺.

Compound 4916-(6-aminopyridin-2-yl)-N2-(3,5-difluorophenyl)-N4-(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.10-8.07 (m, 1H), 7.93-7.86 (m, 1H), 7.54-7.41(m, 2H), 7.25-7.22 (m, 1H), 6.69-6.65 (m, 1H), 4.42-4.25 (m, 2H). LC-MS:m/z 398.2 (M+H)⁺.

Compound 4926-(6-aminopyridin-2-yl)-N2-(3-fluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.04-8.00 (m, 1H), 7.83 (br, 2H), 7.40-7.37 (m,1H), 7.33-7.28 (m, 1H), 7.18-7.16 (m, 1H), 6.79 (t, 1H), 4.51-4.25 (m,1H), 1.29 (d, 6H). LC-MS: m/z 340.2 (M+H)⁺.

Compound 4936-(6-amino-3-fluoropyridin-2-yl)-N2-(tert-butyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamineStep 1: Preparation of (E)-2-(tert-butyl)-1-(diaminomethylene)guanidine

To a mixture of 1-phenyl-2-cyanoguanidine (10 g, 0.119 mol) inethanol/water (176.5 mL/70.6 mL) was added CuSO₄.5H₂O (14.9 g, 0.059mol), followed by 2-methylpropan-2-amine (11.3 g, 0.155 mol). Themixture was heated to reflux for 16 hours. To the mixture was addedwater (137 mL) and aq.HCl (59.5 mL in 100 mL of water) at 25-30° C. Theresultant mixture was stirred at r.t. for 30 min. Then Na₂S (47.6 g in100 mL of water) was added and stirred for another 30 min. The insolubleCuS was filtered off. The filtrate was cooled to 10° C. and addedaqueous NaOH (27 g NaOH in 100 mL water) dropwise. The mixture wasextracted with dichloromethane (100 mL×3). The aqueous layer wasconcentrated and the residue was added dichloromethane (200 mL) and themixture was stirred for 1 hour and the mixture was filtrated. Thefiltrated was concentrated to give(E)-2-(tert-butyl)-1-(diaminomethylene)guanidine as a brown solid.

¹H NMR (CDCl₃) δ 1.32-1.37 (m, 9H).

Step 2: Preparation ofN2-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-1,3,5-triazine-2,4-diamine

The mixture of (E)-2-(tert-butyl)-1-(diaminomethylene) guanidine (1.2 g,7.6 mmol), methyl 3,6-difluoropicolinate (1.3 g, 7.6 mol) and MeONa (0.9g, 15.2 mol) in MeOH (25 mL) was stirred for 5 hours at r.t. TLC showedthe reaction was completed. The mixture was poured into water (15 mL),extracted with EA (50 mL) for 3 times. The combine organic layer wasdried, concentrated and purified by Prep-HPLC to giveN2-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-1,3,5-triazine-2,4-diamineas a white solid.

¹H NMR (CDCl₃) δ 7.5 (m, 1H), 7.0 (m, 1H), 5.4 (B, 1H), 5.1-5.2 (br s,2H), 4.4 (m, 9H).

Step 3: Preparation ofN²-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

To the mixture ofN²-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-1,3,5-triazine-2,4-diamine(0.4 g, 1.4 mmol), 4-chloro-2-(trifluoromethyl)pyridine (0.31 g, 1.7mmol), Cs2CO3 (0.7 g, 2.1 mmol) and X-phos (0.048 g, 0.07 mmol) indioxane (10 mL) was added Pd(OAc)2 under N2 protection. The reactionmixture was heated to 80 deg and stirred for 2 hours. TLC showed thereaction was completed. the reaction mixture was added water (10 mL),extracted with EA (100 mL) for 3 times. The combine organic layer wasdried and concentrated. The residue was purified by a standard method togiveN²-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine.

¹H NMR (CDCl₃) δ 8.6-8.4 (m, 2H), 7.65 (m, 1H), 7.5-7.4 (m, 2H), 7.1 (m,1H), 5.7 (m, 1H), 1.45 (m, 9H).

Step 4: Preparation of6-(6-amino-3-fluoropyridin-2-yl)-N2-(tert-butyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine Compound 494

To the solution ofN²-(tert-butyl)-6-(3,6-difluoropyridin-2-yl)-N⁴-(2-(trifluoromethyl)pyridine-4-yl)-1,3,5-triazine-2,4-diamine(300 mg, 0.7 mmol) and CuI (134 mg, 0.7 mmol) in THF (5 mL) was addedsat.NH₃/EtOH (15 mL) solution. The reaction mixture was stirred in aseal reactor at 130 deg for 10 hours. LCMS showed the reaction wascompleted. The solvent was removed and the residue was purified by astandard method to give6-(6-amino-3-fluoropyridin-2-yl)-N²-(tert-butyl)-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine.

¹H NMR (CDCl₃) δ 8.63 (m, 1H), 8.45 (m, 1H), 7.85 (m, 1H), 7.5-7.4 (m,1H), 6.75 (m, 1H), 1.5 (m, 9H).

According to the general strategy outlined in Scheme 3, step 2, thefollowing intermediates were prepared:

6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione

LCMS: m/z 260.1 (M+H)⁺.

Methyl6-(4,6-dioxo-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 264.2 (M+H)⁺.

6-(4-methoxypyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione

LCMS: m/z 221.1 (M+H)⁺.

According to the general strategy outlined in Scheme 3, step 3, thefollowing intermediates were prepared:

2,4-dichloro-6-(4-(trifluoromethyl)-pyrimidin-2-yl)-1,3,5-triazine

LCMS: m/z 296.0 (M+H)⁺.

2,4-Dichloro-6-(6-difluoromethyl-pyridin-2-yl)-[1,3,5]triazine

LCMS: m/z 277.0 (M+H)⁺.

2,4-Dichloro-6-[6-(1,1-difluoroethyl)-pyridin-2-yl]-[1,3,5]triazine

LCMS: m/z 290.9 (M+H)⁺.

Methyl 6-(4,6-dichloro-1,3,5-triazin-2-yl)-pyridin-2-ylcarbamate

LCMS: m/z 300.1 (M+H)⁺.

2,4-Dichloro-6-(4-methoxypyridin-2-yl)-1,3,5-triazine

LCMS: m/z 257.1 (M+H)⁺.

According to the general strategy outlined in Scheme 3, steps 4-5, thefollowing compounds were prepared from appropriate reagents andintermediates:

Compound 494 N-[2-(1,1-Difluoro-ethyl)-pyridin-4-yl]-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67 (s, 1H), 8.51-8.18 (m, 3H), 7.97-7.73 (m,2H), 4.51-4.32 (m, 1H), 1.97 (t, J=18.8 Hz, 2H), 1.32 (d, J=6.4 Hz, 6H).LC-MS: m/z 440.3 (M+H)⁺.

Compound 4953-[4-(6-Chloro-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-2,2-dimethyl-propan-1-ol

¹H NMR (METHANOL-d₄) δ 8.63-8.45 (m, 3H), 8.44-7.99 (m, 2H), 7.97-7.62(m, 1H), 3.49 (s, 1H), 3.43 (s., 1H), 3.40 (s, 1H), 3.23 (s., 1H), 0.98(d., J=6.4 Hz, 6H). LC-MS: m/z 454.3 (M+H)⁺.

Compound 4962-{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.66 (s, 1H), 8.29-8.11 (m, 3H), 7.88 (s, 1H),7.58-7.56 (m, 1H), 4.40-4.29 (m., 1H), 1.49 (s, 6H), 1.25 (d., J=6.4 Hz,6H). LC-MS: m/z 434.3 (M+H)⁺.

Compound 4973-[4-(6-Chloro-pyridin-2-yl)-6-isopropylamino-[1,3,5]triazin-2-ylamino]-N-cyclopropylmethyl-benzenesulfonamide

¹H NMR (METHANOL-d₄) δ 8.70 (s, 1H), 8.50 (m, 1H), 8.14-8.10 (m, 1H),7.82-7.80 (m, 1H), 7.69-7.67 (m., 2H), 7.58 (m, 1H), 4.42 (m, 1H),2.78-2.76 (d., J=6.8 Hz, 2H), 1.36-1.28 (d, J=10 Hz, 6H), 0.87-0.81 (m,1H), 0.43-0.38 (m, 2H), 0.10-0.07 (m, 2H). LC-MS: m/z 474.3 (M+H)⁺.

Compound 4985-[4-(6-Chloro-pyridin-2-yl)-6-(2,2-dimethyl-propylamino)-[1,3,5]triazin-2-ylamino]-nicotinonitrile

1H NMR (METHANOL-d₄) δ 9.01-8.94 (m, 2H), 8.53-8.41 (m, 2H), 8.00-7.96(m, 1H), 7.62-7.60 (m, 1H), 3.35 (s, 3H), 1.00 (s, 9H). LC-MS: m/z 395.2(M+H)⁺.

Compound 4996-(6-Chloro-pyridin-2-yl)-N-(2-methoxy-1-methyl-ethyl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.62-8.43 (m, 3H), 8.25-8.61 (m, 3H), 4.40-4.36(m, 1H), 3.56-3.48 (m, 2H), 3.47 (s, 3H), 1.32-1.26 (s, 3H). LC-MS: m/z440.3 (M+H)⁺.

Compound 5001-[4-(2-Fluoro-pyridin-4-ylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ yielded the title compound.

¹H NMR (METHANOL-d₄) δ 8.79-8.81 (d, J=8 Hz, 1H), 8.37-8.43 (m, 1H),8.20-8.24 (m, 2H), 7.56-7.72 (m, 2H), 3.65 (s, 2H), 1.36 (s, 6H). LC-MS:m/z 424.2 (M+H)⁺.

Compound 501N-Isopropyl-N′-(6-methyl-pyridazin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ yielded the title compound.

¹H NMR (METHANOL-d₄) δ 9.30-8.85 (m, 2H), 8.78-8.80 (d, J=8 Hz, 1H),8.29-8.28 (m, 1H), 8.07-8.15 (m, 1H), 4.36-4.55 (m, 1H), 2.87 (s, 3H),1.38-1.41 (m, 6H). LC-MS: m/z 391.2 (M+H)⁺.

Compound 5024-[4-(6-Chloro-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl3-d₆) δ 8.51-8.55 (m, 2H), 8.27 (d, J=7.6 Hz, 1H), 7.77 (t,J=8 Hz, 1H), 7.45-7.50 (m, 2H), 7.28-7.33 (m., 1H), 5.65 (d, J=7.6 Hz,1H), 3.95-4.11 (m, 3H), 2.88-2.93 (m., 2H), 2.02 (d, J=11.2 Hz, 2H),1.41-1.51 (m, 11H). LC-MS: m/z 552.0 (M+H)⁺.

Compound 503N-(5-Fluoro-pyridin-3-yl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.66-8.62 (m, 2H), 8.54 (br, 1H), 8.17 (t, J=7.8Hz, 1H), 8.09-8.05 (m, 1H), 7.93 (d, J=7.6 Hz, 1H), 4.24-4.21 (m, 1H),1.26 (d, J=4.2 Hz, 6H). LC-MS: m/z 394.2 (M+H)⁺.

N-(6-Fluoro-pyridin-3-yl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.53-8.50 (m, 2H), 8.46-8.24 (m, 1H), 8.07 (t,J=7.8 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 6.97-6.94 (m, 1H), 4.35-4.13 (m,1H), 1.19 (d, J=6.4 Hz, 6H). LC-MS: m/z 394.1 (M+H)⁺.

Compound 504N-(3-Oxa-bicyclo[3.1.0]hex-6-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.60 (dd, J=8.0 Hz, 2.0, 1H) 8.53 (dd, J=5.6 Hz,1.6, 1H), 8.34 (s, 1H), 8.26-8.21 (m, 2H), 8.01-7.97 (m, 1H), 4.10 (d,J=7.4 Hz, 2H), 3.80 (d, J=8.4 Hz, 2H), 2.80-2.77 (m, 1H), 2.06 (s, 2H).LC-MS: m/z 484.3 (M+H)⁺.

Compound 5054-[4-(3-Oxa-bicyclo[3.1.0]hex-6-ylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridine-2-carbonitrile

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 8.69-8.51 (m, 3H), 8.24-8.20 (m, 1H), 8.09-7.98(m, 2H), 4.12 (d, J=9.2 Hz, 2H), 3.84 (d, J=8.4 Hz, 2H). 2.75 (s, 1H),2.02 (s, 2H). LC-MS: m/z 441.3 (M+H)⁺.

Compound 506N-(6-Fluoro-pyridin-3-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.69-8.61 (m, 2H), 8.38 (br, 1H), 8.16 (t, J=8.0Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.05 (dd, J=6.4 Hz, 2.4, 1H), 4.04 (d,J=8.4 Hz, 2H), 3.78 (d, J=8.4 hz, 2H), 2.64 (s, 1H), 1.94 (s, 1H).LC-MS: m/z 433.9 (M+H)⁺.

N-(2-Fluoro-pyridin-4-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.68-8.66 (m, 1H), 8.24-7.97 (m, 4H), 7.50 (d,J=5.2 Hz, 1H), 4.12 (d, J=8.4 Hz, 2H), 3.83 (d, J=8.0 Hz, 2H), 2.71 (s,1H), 2.05-1.99 (m, 2H). LC-MS: m/z 433.9 (M+H)⁺.

Compound 507N-(3-Oxa-bicyclo[3.1.0]hex-6-yl)-N′-(5-trifluoromethyl-pyridin-3-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.38 (br, 1H), 8.82-8.42 (m, 4H), 8.24 (d, J=8.4Hz, 1H), 4.05 (d, J=8.4 Hz, 2H), 3.79 (d, J=8.4 Hz, 2H), 2.81 (s, 1H),2.15 (s, 2H). LC-MS: m/z 484.3 (M+H)⁺.

Compound 508N-(2-Fluoro-pyridin-4-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 8.48-8.50 (d, J=7.2 Hz, 1H), 7.97-8.15 (m, 3H),7.79-7.96 (m, 1H), 7.48-7.54 (m, 1H), 4.13-4.15 (d, J=8.8 Hz, 2H),3.83-3.85 (d, J=8 Hz, 2H), 2.78 (s, 1H), 2.07-2.10 (d, J=13.2 Hz, 2H).LC-MS: m/z 400.1 (M+H)⁺.

Compound 509N-(3-Oxa-bicyclo[3.1.0]hex-6-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 8.47-8.66 (m, 2H), 8.07-8.28 (m, 3H), 7.76-7.78(d, J=8 Hz, 1H), 4.06-4.14 (m, 2H), 3.80-3.82 (d, J=8.4 Hz, 2H), 2.82(s, 1H), 2.04-2.16 (m, 2H). LC-MS: m/z 450.1 (M+H)⁺.

Compound 510N-(3-Oxa-bicyclo[3.1.0]hex-6-yl)-N′-(5-trifluoromethyl-pyridin-3-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 9.05-9.20 (m, 1H), 8.36-8.45 (m, 3H), 7.96-7.97(m, 1H), 7.57-7.60 (d, J=7.6 Hz, 1H), 4.04-4.06 (d, J=8.4 Hz, 2H),3.75-3.77 (d, J=8.4 Hz, 2H), 2.78 (s, 1H), 1.94 (s, 2H). LC-MS: m/z450.1 (M+H)⁺.

Compound 5116-(6-Chloro-pyridin-2-yl)-N-(5-fluoro-pyridin-3-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.50-10.60 (m, 1H), 8.79-8.91 (m, 1H), 8.43-8.48 (m,2H), 8.19-8.29 (m., 2H), 8.05-8.11 (m, 1H), 7.67-7.73 (m, 1H), 3.95-4.06(m, 2H), 3.68-3.70 (m, 2H), 3.32-3.33 (m, 1H), 1.95 (s, 2H). LC-MS: m/z400.2 (M+H)⁺.

Compound 5126-(6-Chloro-pyridin-2-yl)-N-(6-fluoro-pyridin-3-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.36 (br, 1H), 8.76-8.93 (m, 1H), 8.30-8.43 (m, 3H),8.04-8.10 (m., 1H), 7.70-7.72 (m, 1H), 7.13-7.20 (m, 1H), 3.96-3.94 (m,2H), 3.65-3.70 (m, 2H), 3.32-3.33 (m, 1H), 2.09 (s, 2H). LC-MS: m/z400.2 (M+H)⁺.

Compound 5136-(6-Chloro-pyridin-2-yl)-N-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.51-8.14 (m, 3H), 7.96-7.59 (m, 3H), 4.52-4.26(m, 1H), 1.97 (t, J=18.8 Hz, 2H), 1.31 (t., J=6.4 Hz, 6H). LC-MS: m/z406.3 (M+H)⁺.

Compound 5142-{4-[4-(6-Chloro-pyridin-2-yl)-6-isopropylamino-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.48-8.30 (m, 3H), 7.99-7.95 (m, 1H), 7.77-7.61(m, 2H), 4.51-4.37 (m, 1H), 1.57 (s., 6H), 1.30 (d., J=6.4 Hz, 6H).LC-MS: m/z 400.3 (M+H)⁺.

Compound 515N-(3,5-Difluoro-phenyl)-N′-(2-methyl-cyclopropyl)-6-pyridin-2-yl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.72-8.48 (m, 2H), 8.08-7.57 (m, 4H), 6.58 (s,1H), 2.27-2.57 (m, 1H), 1.20 (s., 3H), 0.99-0.75 (m, 2H), 0.64-0.51 (s,H). LC-MS: m/z 455.2 (M+H)⁺.

Compound 516N-(2-Methyl-cyclopropyl)-6-pyridin-2-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.73-7.98 (m, 6H), 7.61-7.58 (m, 1H), 2.79-2.54(m, 1H), 1.20 (d, J=6.0 Hz, 3H), 0.85-0.81 (m., 1H), 0.71-0.67 (m, 2H).LC-MS: m/z 388.3 (M+H)⁺.

Compound 517N-(2,2-Dimethyl-propyl)-6-pyridin-2-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.75-8.49 (m, 4H), 8.03-7.76 (m, 1H), 7.62-7.59(m, 2H), 3.41 (s, 2H), 0.99 (s., 9H). LC-MS: m/z 404.3 (M+H)⁺.

Compound 5183-[4-(6-Chloro-pyridin-2-yl)-6-isopropylamino-[1,3,5]triazin-2-ylamino]-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide

¹H NMR (DMSO-d₆) δ 8.74 (s, 1H), 8.70-8.40 (m, 1H), 8.37-8.30 (m, 1H),8.30-8.11 (m, 1H), 8.09-8.01 (m., 1H), 7.84-7.82 (m, 1H), 7.69 (m, 1H),7.54 (m, 1H), 7.48-7.44 (m, 1H), 4.33-4.22 (m, 1H), 3.72-3.62 (m, 2H),1.23-1.20 (d, J=12 Hz, 6H). LC-MS: m/z 501.8 (M+H)⁺.

Compound 5201-[4-(3,5-Difluoro-phenylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.66-8.68 (m, 1H), 8.19-8.23 (m, 1H), 7.96-7.98(m, 1H), 7.51-7.57 (m., 2H), 6.57-6.60 (m, 1H), 3.56-3.61 (d, J=20 Hz,2H), 1.29 (s, 6H). LC-MS: m/z 441.2 (M+H)⁺.

Compound 521N-(2,2-Dimethyl-propyl)-N′-pyrimidin-5-yl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.28-9.31 (m, 2H), 8.79-8.82 (m, 1H), 8.67-8.69(m, 1H), 8.19-8.23 (m, 1H), 7.96-7.98 (m, 1H), 3.37-3.45 (m, 1H),3.30-3.37 (m, 1H), 1.01 (s, 9H). LC-MS: m/z 405.3 (M+H)⁺.

Compound 522N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine-2,4-diamine

Using the standard procedure described above except replace t-BuONa byCs₂CO₃ to give the title compound.

¹H NMR (DMSO-d₆): δ 10.63-10.81-10.95 (m, 1H), 9.36-9.39 (m, 1H), 8.73(s, 1H), 8.08-8.56 (m, 3H), 7.84-7.85 (m, 1H), 4.14-4.19 (m, 1H),1.20-1.24 (m, 6H). LC-MS: m/z 444.8 (M+H)⁺.

Compound 523N2-neopentyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine-2,4-diamine

Using the standard procedure described above except replace t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (DMSO-d₆): δ 10.70-10.95 (m, 1H), 9.23 (d, J=6.0 Hz, 1H), 8.86(s, 1H), 8.36-8.76 (m, 3H), 7.64-7.66 (m, 1H), 3.29-3.35 (m, 2H),0.90-1.0.95 (m, 9H). LC-MS: m/z 473.2 (M+H)⁺.

Compound 524N-(2-Methoxy-propyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

1H NMR (METHANOL-d₄) δ 8.75-8.77 (m, 1H), 8.66-8.67 (m, 1H), 8.50-8.52(m, 1H), 8.36-8.38 (m, 1H), 8.1.7-8.18 (m, 1H), 7.91-7.92 (m., 1H),3.52-3.80 (m, 3H), 3.45 (s., 3H), 1.27-1.255 (d., J=6.0 Hz, 2H). LC-MS:m/z 474.2 (M+H)⁺.

Compound 526N-(2-Methoxy-1-methyl-ethyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.69-8.67 (m, 1H), 8.61-8.29 (m, 2H), 8.22-7.87(m, 3H), 4.62-4.37 (m, 1H), 3.57-3.46 (m., 2H), 3.31 (s, 3H), 1.33-1.30(m, 3H). LC-MS: m/z 473.9 (M+H)⁺.

Compound 5272-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-propan-1-ol

¹H NMR (METHANOL-d₄) δ 8.73-8.48 (m, 3H), 8.23-7.92 (m, 3H), 4.62-4.29(m, 1H), 3.70-3.67 (m, 2H), 1.335-1.319 (d, J=6.4 Hz, 3H). LC-MS: m/z459.9 (M+H)⁺.

Compound 528N-(3-Methoxy-propyl)-N′-(2-trifluoromethyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67-8.69 (m, 1H), 8.50-8.61 (m, 2H), 8.19-8.23(m, 1H), 7.93-7.99 (m, 2H), 3.61-3.69 (m, 2H), 3.54-3.56 (m, 2H),3.30-3.37 (m, 1H), 1.93-1.99 (m, 2H). LC-MS: m/z 474.3 (M+H)⁺.

Compounds 529N-(Tetrahydro-furan-3-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.66-8.68 (m, 1H), 8.62-8.66 (m, 1H), 8.49-8.51(m, 1H), 8.18-8.22 (m, 2H), 7.95-7.97 (m, 1H), 4.60-4.66 (m, 1H),3.99-4.05 (m, 2H), 3.79-3.82 (m, 2H), 2.04-2.39 (m, 2H). LC-MS: m/z472.3 (M+H)⁺.

Compounds 5302,2-Dimethyl-3-[4-(6-trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-propan-1-ol

¹H NMR (METHANOL-d₄) δ 8.74-8.70 (m, 1H), 8.67-8.52 (m, 2H), 8.29-7.90(m, 3H), 3.51-3.41 (m, 2H), 3.34-3.33 (m., 1H), 3.23 (s, 1H), 1.03-0.92(m, 6H). LC-MS: m/z 488.3 (M+H)⁺.

Compound 531N-(2-Methyl-tetrahydro-furan-2-ylmethyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.24 (m, 3H), 8.23-7.84 (m, 3H), 3.97-3.90(m, 2H), 3.78-3.58 (m, 2H), 2.03-1.97 (m., 2H), 1.78-1.74 (m, 1H), 1.31(s, 3H). LC-MS: m/z 500.3 (M+H)⁺.

Compound 532N-(2-Methyl-cyclopropyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.70-8.19 (m, 3H), 8.06-7.98 (m, 3H), 2.67-2.64(m, 1H), 1.25-1.21 (m, 3H), 1.21-0.98 (m., 1H), 0.88-0.80 (m, 1H),0.62-0.51 (m, 1H). LC-MS: m/z 456.2 (M+H)⁺.

Compound 533N-(1-Methyl-cyclopropyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.85-8.65 (m, 2H), 8.48 (s, 1H), 8.20-8.16 (m,1H), 7.96-7.82 (m, 2H), 1.55 (s, 3H), 0.93-0.90 (m, 2H), 0.85-0.82 (m,2H). LC-MS: m/z 456.2 (M+H)⁺.

Compound 5344-[4-Isopropylamino-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridine-2-carbonitrile

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 9.33-9.31 (m, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.47(dd, J=7.2 Hz, 5.6 Hz, 1H), 8.07 (d, J=4.8 Hz, 1H), 7.96-7.95 (m, 1H),4.30-4.27 (m, 1H), 1.32 (dd, J=12 Hz, 6.0 Hz, 6H). LC-MS: m/z 402.2(M+H)⁺.

Compound 535N-(6-Fluoro-pyridin-3-yl)-N′-isopropyl-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 9.30 (d, J=4.8 Hz, 1H), 8.62-8.53 (m, 2H), 8.05(d, J=5.2 Hz, 1H), 7.08-7.07 (m, 1H), 4.25-4.22 (m, 1H), 1.28 (dd,J=10.8 Hz, 6.4 Hz, 6H). LC-MS: m/z 395.2 (M+H)⁺.

Compound 536N-Isopropyl-N′-(5-trifluoromethyl-pyridin-3-yl)-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 9.31-9.33 (d, J=4.8 Hz, 1H), 8.98-9.11 (m, 1H),8.52 (s, 1H), 8.06-8.07 (d, J=4 Hz, 1H), 4.26-4.63 (m, 2H), 1.28-1.34(m, 6H). LC-MS: m/z 445.3 (M+H)⁺.

Compound 537N-(2-Fluoro-pyridin-4-yl)-N′-isopropyl-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ to yield the title compound.

¹H NMR (METHANOL-d₄) δ 9.41-9.42 (m, 1H), 8.14-8.20 (m, 2H), 7.59-7.82(m, 1H), 4.35-4.38 (m, 2H), 1.32-1.41 (m, 6H). LC-MS: m/z 395.2 (M+H)⁺.

Compound 5391-(4-(5,6-difluoropyridin-3-ylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.61-8.75 (m, 1H), 8.01-8.43 (m, 4H), 3.48 (s,2H), 1.21 (s, 6H). LC-MS: m/z 442.2 (M+H)⁺.

Compound 5401-[4-(6-Fluoro-5-methyl-pyridin-3-ylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.94 (s, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.35 (t,J=8.0 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.65-7.86 (m, 3H), 4.41-4.48 (m,1H), 3.20 (d, J=7.2 Hz, 2H), 1.37 (d, J=6.4 Hz, 6H), 0.98-1.06 (m, 1H),0.53-0.57 (m, 2H), 0.17-0.21 (m, 2H). LC-MS: m/z 493.1 (M+H)⁺.

Compound 5411-{[4-(3,5-Difluoro-phenylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-methyl}-cyclopropanol

¹H NMR (DMSO-d₆) δ 8.628-8.543 (m, 1H), 8.336-8.281 (m, 1H), 8.107-8.088(d, J=7.6 Hz, 2H), 7.788-7.767 (d, J=8.4 Hz, 1H), 1.30 (d, J=6.2 Hz,1H), 6.842-6.797 (m, 1H), 5.503-5.428 (d, J=30 Hz, 1H), 3.629-3.567 (m,2H), 0.666-0.584 (m, 2H). LC-MS: m/z 439.0 (M+H)⁺.

Compound 5422-{3-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.82-8.79 (m, 1H), 8.77-8.75 (m, 1H), 8.48-8.42(m, 1H), 8.23-8.20 (m, 1H), 7.63-7.57 (m, 3H), 4.43-4.26 (m, 1H),1.656-1.573 (d, J=33.2 Hz, 3H), 1.288-1.188 (d, J=40 Hz 3H). LC-MS: m/z433.1 (M+H)⁺.

Compound 543N-(1-Methyl-1H-pyrazol-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.69 (m, 1H), 8.58-8.31 (m, 4H), 8.19-7.99(m, 2H), 7.70-7.65 (m, 1H), 3.92 (s, 3H). LC-MS: m/z 481.37 (M+H)⁺.

Compound 544N-(2-Methyl-2H-pyrazol-3-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.75-8.32 (m, 4H), 8.25-8.00 (m, 2H), 7.53 (s,1H), 6.44 (s, 1H), 3.83 (s, 3H). LC-MS: m/z 482.3 (M+H)⁺.

Compound 546N2-(thiazol-5-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.7-8.9 (m, 1H), 8.65 (m, 1H), 8.35-8.55 (m, 1H),8.05-8.3 (m, 2H), 8.0 (m, 1H), 7.75 (m, 1H). LC-MS: m/z 485.2 (M+H)⁺.

Compound 547N-(Tetrahydro-furan-3-ylmethyl)-N′-(2-trifluoromethyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.78-8.76 (d, J=8 Hz 1H), 8.70-8.68 (d, J=5.6 Hz1H), 8.53-8.52 (m, 1H), 8.43-8.37 (m, 1H), 8.22-8.20 (m, 1H), 7.92-7.91(m, 1H), 3.95-3.93 (m, 1H), 3.92-3.88 (m, 1H), 3.86-3.85 (m, 1H),3.78-3.77 (m, 3H), 2.73-2.71 (m, 1H), 2.18-2.15 (m, 1H), 1.77-1.75 (m,1H). LC-MS: m/z 486.2 (M+H)+.

Compound 5483-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-butan-2-ol

¹H NMR (METHANOL-d₄) δ 8.60-8.40 (m, 3H), 8.13-7.80 (m, 3H), 4.32-4.05(m, 1H), 3.88-3.79 (m, 1H), 1.23-1.12 (m, 6H). LC-MS: m/z 474.3 (M+H)⁺

Compound 549N-(3-Methyl-oxetan-3-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.54 (m, 1H), 8.49-8.52 (m, 2H), 8.25-8.21(m, 1H), 8.14-7.89 (m, 2H), 4.65-4.64 (m, 2H), 1.85 (s, 3H). LC-MS: m/z472.3 (M+H)⁺

Compound 550N-(3-Methyl-oxetan-3-ylmethyl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.72-8.52 (m, 3H), 8.26-7.99 (m, 3H), 4.74-4.67(m, 2H), 4.45-4.42 (m, 2H), 3.87-3.82 (m, 2H), 1.43 (s, 3H). LC-MS: m/z486.3 (M+H)⁺

Compound 551N-(2-Difluoromethyl-pyridin-4-yl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.68 (m, 1H), 8.53 (s, 1H), 8.44 (m, 1H),8.23-7.78 (m, 3H), 6.84-6.56 (m., 1H), 4.31 (m, 1H), 1.36-1.34 (d, J=8Hz, 6H). LC-MS: m/z 426.2 (M+H)⁺

Compound 5522-Methyl-3-[4-(6-trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-propan-1-ol

¹H NMR (METHANOL-d₄) δ 8.72-8.69 (m, 1H), 8.56-8.49 (m, 2H), 8.28-7.96(m, 3H), 4.64-3.29 (m, 4H), 2.07-2.03 (m, 1H), 1.04-0.998 (m, 3H).LC-MS: m/z 474.2 (M+H)⁺

Compound 5545-[4-(2,2-Dimethyl-propylamino)-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-ylamino]-nicotinonitrile

Using the standard procedure described above except replacing t-BuONa byCs₂CO₃ yielded the title compound.

¹H NMR (MeOH-d₄) δ 9.42-9.46 (m, 1H), 8.73-9.25 (m, 3H), 8.21-8.26 (m,1H), 3.49-3.51 (m, 2H), 1.00-1.07 (m, 9H). LC-MS: m/z 430.3 (M+H)⁺.

Compound 555N-Isopropyl-N′-(1-propyl-1H-pyrazol-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67-8.65 (m, 1H), 8.30-7.98 (m, 3H), 7.70-7.60(m, 1H), 4.50-4.20 (m, 1H), 4.13-4.10 (m., 2H), 1.92-1.89 (m, 2H),1.35-1.29 (m, 6H), 0.96-0.93 (t, 3H). LC-MS: m/z 407.3 (M+H)⁺

Compound 556N-(7-Oxa-bicyclo[2.2.1]hept-2-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.48 (m, 3H), 8.24-7.93 (m, 3H), 4.87-4.86(m, 1H), 4.70-4.605 (m, 1H), 4.43-4.18 (m, 1H), 2.35-1.99 (m, 2H),1.78-1.23 (m, 4H). LC-MS: m/z 498.2 (M+H)⁺

Compound 557N²-((tetrahydrofuran-3-yl)methyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (MeOH-d₄) δ 9.36-9.42 (m, 1H), 8.50-8.69 (m, 2H), 8.20-8.21 (m,1H), 7.93-8.13 (m, 1H), 3.64-3.98 (m, 6H), 2.71-2.77 (m, 1H), 2.12-2.27(m, 1H), 1.73-1.81 (m, 1H). LC-MS: m/z 487.3 (M+H)⁺.

Compound 558N²-(1-methoxypropan-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (MeOH-d₄) δ 9.31 (d, J=4.8 Hz, 1H), 8.30-8.66 (m, 2H), 7.87-8.21(m, 2H), 4.36-4.67 (m, 1H), 3.49 (s, 3H), 1.28-1.34 (m, 3H). LC-MS: m/z475.3 (M+H)⁺.

Compound 559N-Isopropyl-N′-[2-(1-methoxy-cyclopropyl)-pyridin-4-yl]-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.69-8.71 (d, J=8 Hz, 1H), 8.18-8.31 (m, 3H),7.93-7.98 (m, 1.3H), 7.58-7.59 (d, J=3.6 Hz, 0.7H), 4.34-4.62 (m, 1H),3.39 (s, 3H), 1.33-1.34 (d, J=6 Hz, 1H), 1.23-1.28 (m, 4H). LC-MS: m/z446.2 (M+H)⁺

Compound 5601-[4-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-6-(3,5-difluoro-phenylamino)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.65-8.88 (d, J=7.6 Hz, 1H) 8.30-8.35 (d, J=20Hz, 1H), 8.10-8.12 (d, J=8 Hz, 1H), 7.50-7.58 (m, 2H), 6.86-6.90 (m,1H), 3.58-3.64 (d, J=24 Hz, 1H), 2.13-2.25 (m, 3H), 1.35-1.37 (d, J=6.8Hz, 6H). LC-MS: m/z 437.1 (M+H)⁺

Compound 561N-(3-Chloro-5-methanesulfonyl-phenyl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

1H NMR (METHANOL-d₄) δ 8.70-8.67 (m, 2H), 8.24-8.17 (m, 1H), 8.04 (m,1H), 7.97-7.95 (m, 1H), 7.58-7.55 (s., 1H), 4.34-4.28 (m, 1H), 3.19 (s,3H), 1.33-1.31 (d, J=6.4 Hz, 6H). LC-MS: m/z 487.2 (M+H)⁺

Compound 5622-Methyl-2-[4-(6-trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-propan-1-ol

¹H NMR (METHANOL-d₄) δ 8.70-8.68 (d, J=8 Hz 1H), 8.64-7.88 (m, 5H),8.53-8.52 (m, 1H), 3.83 (s, 3H), 1.523-1.496 (d, J=10.8 Hz 6H). LC-MS:m/z 474.3 (M+H)+.

Compound 563N-(2-Cyclopropyl-pyridin-4-yl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.78-8.76 (m, 1H), 8.48-8.35 (m, 2H), 8.17-8.06(m, 3H), 4.39-4.36 (m, 1H), 1.49-1.38 (m, 8H), 1.21-1.19 (m, 2H). LC-MS:m/z 416.1 (M+H)⁺.

Compound 564N-tert-Butyl-N′-(2-cyclopropyl-pyridin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.68-8.66 (m, 1H), 8.21-8.19 (m, 2H), 7.98-7.64(m, 3H), 2.15-2.11 (m, 1H), 1.59 (s, 9H), 1.11-1.01 (m, 4H). LC-MS: m/z430.1 (M+H)⁺.

Compound 565N-(2-Cyclopropyl-pyridin-4-yl)-N′-(1-methyl-cyclopropyl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.69-8.67 (m, 1H), 8.25-8.19 (m, 2H), 8.01-7.86(m, 3H), 2.15-2.11 (m, 1H), 1.57-1.56 (m, 1H), 1.17-1.12 (m, 2H),1.08-1.02 (m, 2H), 0.94-0.90 (m, 2H), 0.87-0.85 (m, 2H). LC-MS: m/z428.1 (M+H)⁺.

Compound 566{1-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-cyclopropyl}-methanol

¹H NMR (METHANOL-d₄) δ 8.74-8.69 (m, 2H), 8.52-8.48 (m, 1H), 8.25-7.58(m, 3H), 3.79 (s, 2H), 1.02-0.95 (m, 4H). LC-MS: m/z 494.2 (M+H)⁺.

Compound 567N-tert-Butyl-N′-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.72-8.44 (m, 3H), 8.25-7.77 (m, 3H), 2.05-1.95(m, 3H), 1.58 (s, 9H). LC-MS: m/z 454.1 (M+H)⁺.

Compound 5682-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-cyclopropanol

¹H NMR (METHANOL-d₄) δ 8.31-8.90 (m, 3H), 8.15-8.30 (m, 2H), 7.93-8.05(m, 1H), 3.43-3.55 (m, 1H), 2.90-3.10 (m, 1H), 1.10-1.25 (m, 1H),0.89-0.99 (m, 1H). LC-MS: m/z 458.2 (M+H)⁺.

Compound 5692-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-cyclopropanol

¹H NMR (METHANOL-d₄) δ 8.35-8.90 (m, 3H), 8.13-8.34 (m, 2H), 7.97-8.05(m, 1H), 3.47-3.55 (m, 1H), 2.72-3.01 (m, 1H), 1.08-1.25 (m, 1H),0.90-0.99 (m, 1H). LC-MS: m/z 458.2 (M+H)⁺.

Compound 570N2-(3-fluoro-5-(methylsulfonyl)phenyl)-N4-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.70-8.62 (m, 2H), 8.21-7.84 (m, 3H), 7.35-7.33(m, 1H), 4.34-4.31 (m, 1H), 3.16 (s, 3H), 1.31 (dd, 6H). LC-MS: m/z470.0 (M+H)⁺.

Compound 571N2-isobutyl-N4-(3-(methylsulfonyl)phenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.7-8.9 (m, 2H), 8.3-8.5 (m, 1H), 8.0-8.2 (m,1H), 7.6-7.86 (m, 3H), 3.5 (m, 2H), 3.15 (S, 3H), 1.0-1.1 (d, J=16 Hz,6H). LC-MS: m/z 467.1 (M+H)⁺.

Compound 572N2-(2-chloropyridin-4-yl)-N4-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₄) δ 10.2-10.5 (m, 1.0H), 8.85-8.65 (m, 1H), 8.6 (m, 1H),8.25-8.45 (m, 3H), 8.1 (m, 1H), 7.2 (m, 1H), 4.1-4.4 (m, 1H), 1.2 (d,J=6.4 Hz, 6H). LC-MS: m/z 410.1 (M+H)⁺.

Compound 5731-[4-[2-(1,1-Difluoro-ethyl)-pyridin-4-ylamino]-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.72-8.42 (m, 3H), 8.24-7.74 (m, 3H), 3.64-3.60(m, 2H), 2.05-1.94 (m, 3H), 2.34-1.91 (m, 4H), 1.30-1.29 (m, 6H). LC-MS:m/z 492.1 (M+Na)⁺.

Compound 5741-{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-propan-1-one

¹H NMR (METHANOL-d₄) δ 8.69 (s, 0.7H), 8.63-8.64 (d, J=8 Hz, 1H),8.38-8.40 (dd, J₁=5.2 Hz, J₂=9.2 Hz, 1H), 8.13-8.18 (q, J=8 Hz, 1H),7.78-8.03 (m, 2H), 4.22-4.36 (m, 1H), 3.12-3.16 (m, 2H), 1.25-1.29 (m,6H), 1.11-1.14 (m, 3H). LC-MS: m/z 375.1 (M+H)⁺.

Compound 5766-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-N-[2-(1,1-difluoro-ethyl)-pyridin-4-yl]-N′-isopropyl-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.78-8.80 (d, J=6 Hz, 1H), 8.69-8.71 (d, J=8.4Hz, 2H), 8.26-8.53 (m, 1H), 8.05-8.19 (m, 2H), 4.39-4.60 (m, 1H),2.10-2.24 (m, 6H), 1.40-1.46 (m, 6H). LC-MS: m/z 436.3 (M+H)⁺.

Compound 5774-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylicacid methyl ester

¹H NMR (METHANOL-d₄) δ 8.30-8.78 (m, 3H), 7.82-8.29 (m, 3H), 4.10-4.39(m, 3H), 3.73 (s, 3H), 2.99-3.18 (m, 2H), 2.02-2.16 (m, 2H), 1.53-1.65(m, 2H). LC-MS: m/z 543.3 (M+H)⁺.

Compound 5781-{4-[4-(6-Trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-piperidin-1-yl}-ethanone

¹H NMR (METHANOL-d₄) δ 8.62-8.87 (m, 2H), 8.30-8.60 (m, 2H), 7.88-8.29(m, 2H), 4.31-4.60 (m, 2H), 3.95-4.10 (m, 1H), 3.37-3.43 (m, 1H),2.90-3.19 (m, 1H), 2.10-2.30 (m, 5H), 1.58-1.83 (m, 2H). LC-MS: m/z527.2 (M+H)⁺.

Compound 580N-(1-Methanesulfonyl-piperidin-4-yl)-6-(6-trifluoromethyl-pyridin-2-yl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67-8.93 (m, 2H), 8.38-8.59 (m, 2H), 7.92-8.31(m, 2H), 4.19-4.52 (m, 1H), 3.70-3.88 (m, 2H), 3.08 (t, J=10.4 Hz, 6H),2.93 (s, 3H), 2.18-2.32 (m, 2H), 1.77-1.98 (m, 2H). LC-MS: m/z 563.3(M+H)⁺.

Compound 581N-Isopropyl-N′-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 8.73-8.69 (d, J=17.6 Hz 1H), 8.26-8.16 (m, 3H),8.06-7.97 (m, 1H), 7.63-7.62 (m, 1H), 4.38-4.34 (m, 1H), 1.54-1.52 (s,3H), 1.35-1.26 (m, 6H), 1.18-1.16 (m, 2H), 0.90-0.97 (m, 2H). LC-MS: m/z430.1 (M+H)⁺.

Compound 5826-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-N-isopropyl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.63-8.50 (m, 3H), 8.26-8.09 (m, 1H), 7.97-7.87(m, 2H), 4.50-4.29 (m, 1H), 2.14 (t, J=13.2 Hz, 3H), 1.35 (d, J=8.8 Hz,6H). LC-MS: m/z 440.1 (M+H)⁺.

Compound 5836-(6-(1,1-difluoroethyl)pyridin-2-yl)-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.53 (t, 1H), 8.09 (t, 1H), 7.86-7.84 (m, 1H),7.58-7.56 (m, 1H), 6.60-6.56 (m, 1H), 4.28-4.25 (m, 1H), 2.17-2.04 (m,3H), 1.33-1.29 (m, 6H). LC-MS: m/z 407.2 (M+H)⁺.

Compound 584N2-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(3,5-difluorophenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.51 (t, 1H), 8.01 (t, 1H), 7.84 (t, 1H),7.56-7.54 (m, 1H), 6.56 (t, 1H), 3.42-3.36 (1H), 2.10 (t, 3H), 1.18-1.16(m, 1H), 0.57-0.51 (m, 2H), 0.33-0.29 (m, 2H). LC-MS: m/z 419.2 (M+H)⁺.

Compound 585N2-(tert-butyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(3,5-difluorophenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.85-8.49 (m, 1H), 8.09-8.06 (m, 1H), 7.83 (d,1H), 7.52-7.48 (m, 2H), 6.61-6.56 (m, 1H), 2.10 (t, 3H), 1.53 (s, 9H).LC-MS: m/z 421.1 (M+H)⁺.

Compound 5861-(4-((4-((cyclopropylmethyl)amino)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.62 (d, 1H), 8.16-7.56 (m, 4H), 4.47-4.23 (m,1H), 3.62-3.61 (m, 1H), 1.34-1.04 (m, 10H). LC-MS: m/z 405.2 (M+H)⁺.

Compound 587N2-(tetrahydro-2H-pyran-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄) δ 8.7-8.25 (m, 3H), 8.25-7.7 (m, 3H), 4.4-4.1 (m,1H), 4.0 (m, 2H), 3.65-3.5 (m, 2H), 2.1-2.0 (m, 2H), 1.8-1.6 (m, 2H).LC-MS: m/z 486.3 (M+H)⁺.

Compound 5882-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)cyclopentanol

¹H NMR (METHANOL-d₄) δ 8.85-8.6 (m, 2.0H), 8.5-8.0 (m, 4H), 4.4-4.15 (m,2H), 2.4-1.6 (m, 6H). LC-MS: m/z 486.0 (M+H)⁺.

Preparation of3-[4-(6-Chloro-pyridin-2-yl)-6-isopropylamino-[1,3,5]triazin-2-ylamino]-N-cyclopropyl-benzamideStep 1: Preparation of methyl3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-yl-amino)benzoate

To a solution of4-chloro-6-(6-chloropyridin-2-yl)-N-isopropyl-1,3,5-triazin-2-amine (134mg, 0.47 mmol) in toluene (4 mL) was added methyl 3-aminobenzoate (85.6mg, 0.57 mmol), Cs₂CO₃ (306.9 mg, 0.94 mmol), BINAP (29.33 mg, 0.047mmol) and Pd₂(dba)₃ (43.13 mg, 0.047 mmol). The mixture was purged withnitrogen three times and stirred at 110° C. for 40 min under M.W.irradiation. TLC (PE: EA=1:1) showed the reaction was complete. Themixture was partitioned between H₂O (150 mL) and EA (50 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by combi flash to give methyl3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)benzoate as a yellow solid.

Step 2: Preparation of3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)benzoicacid

To a solution of methyl3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-y-1amino)benzoate (112 mg, 0.28 mmol) in MeOH (2 mL) was added NaOH (0.28mL, 3 N). The mixture was stirred at room temperature for 3 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was concentratedin vacuo. The residue was acidified with 1 N HCl to pH=6 and extractedwith CH₂Cl₂ (50 mL*3). The combined extracts were concentrated to give3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)benzoic acid as a yellow solid.

Step 3:3-[4-(6-Chloro-pyridin-2-yl)-6-isopropylamino-[1,3,5]triazin-2-ylamino]-N-cyclopropyl-benzamide

To a solution of3-(4-(6-chloropyridin-2-yl)-6-(isopropylamino)-1,3,5-triazin-2-ylamino)benzoic acid (104 mg, 0.27 mmol) in DMF (4 mL) was added HATU (205 mg,0.54 mmol), NMM (81.93 mg, 0.81 mmol). The mixture was purged withnitrogen and stirred at room temperature overnight. LCMS showed thereaction was complete. The mixture was poured into brine (150 mL) andextracted with EA (50 mL*2). The combined extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bya standard method to give the title compound.

¹H NMR (METHANOL-d₄) δ 8.57-8.40 (m, 2H), 8.01 (t, J=7.9 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.48-7.40 (m, 2H), 4.33-4.30(m, 1H), 2.89-2.87 (m, 1H), 1.32 (d, J=6.4 Hz, 6H), 0.87-0.82 (m, 2H),0.68-0.64 (m, 2H). LC-MS: m/z 424.2 (M+H)⁺.

Example 8 Preparation of Compounds of Formula I Wherein Ring A isSubstituted Aryl or Heteroaryl

The compounds of this Example are prepared by the general method inScheme 8, set forth below.

Preparation of2-Methyl-1-[4-(2-trifluoromethyl-pyridin-4-ylamino)-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-ylamino]-propan-2-olExample 8, Step 1 Preparation of4-chloro-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-yl]-(2-trifluoromethyl-pyridin-4-yl)-amine

To a solution of2,4-dichloro-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazine (1)(981 mg, 3.31 mmol) in THF (80 mL) was added2-(trifluoromethyl)pyridin-4-amine (4) (590 mg, 3.64 mmol) and NaHCO₃(556 mg, 6.6 mmol). The mixture was stirred at refluxing for 18 hours.The mixture was concentrated and poured to water, extracted with ethylacetate, dried over sodium sulphate, filtered and concentrated to give aresidue, which was purified by SiO₂ chromatography to give4-chloro-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-yl]-(2-trifluoromethyl-pyridin-4-yl)-amine(0.45 g, 32%) as a yellow solid.

LCMS: m/z 422.2 (M+H)⁺

The following intermediate was similarly prepared according to Example8, step 1:

4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine

LCMS: m/z 421.2 (M+H)⁺

4-chloro-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine

LCMS: m/z 416.3 (M+H)⁺

Example 8, Step 22-Methyl-1-[4-(2-trifluoromethyl-pyridin-4-ylamino)-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-ylamino]-propan-2-ol

To a solution of[4-chloro-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-yl]-(2-trifluoromethyl-pyridin-4-yl)-amine(90 mg, 0.21 mmol) in anhydrous THF (2 mL) was added1-amino-2-methyl-propan-2-ol (28.5 mg, 0.32 mmol). The mixture wasstirred at ambient temperature for 4 hour. After concentration, theresidue was purified by a standard method to give2-methyl-1-[4-(2-trifluoromethyl-pyridin-4-ylamino)-6-(4-trifluoromethyl-pyrimidin-2-yl)-[1,3,5]triazin-2-ylamino]-propan-2-ol.

Compound 5892-methyl-1-((4-((2-(trifluoromethyl)pyridin-4-yl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazin-2-yl)amino)propan-2-ol

¹H NMR (MeOH-d₄) δ 9.41-9.48 (m, 1H), 8.49-8.72 (m, 2H), 7.92-8.27 (m,2H), 3.65-3.69 (m, 2H), 1.37 (s, 6H). LC-MS: m/z 475.3 (M+H)⁺.

The following compounds were prepared in a similar manner to thesynthetic sequence in Scheme 8, Steps 1 and 2, using appropriatereagents and synthetic intermediates:

Compound 5902-((4-((2-(trifluoromethyl)pyridin-4-yl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3,5-triazin-2-yl)amino)propan-1-ol

¹H NMR (MeOH-d₄) δ 9.35-9.41 (m, 1H), 8.39-8.64 (m, 2H), 8.18-8.21 (m,1H), 7.93-8.13 (m, 1H), 4.34-4.46 (m, 1H), 3.67-3.80 (m, 2H), 1.31-1.39(m, 3H). LC-MS: m/z 461.3 (M+H)⁺.

Compound 5912-Methyl-3-[4-(6-trifluoromethyl-pyridin-2-yl)-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-ylamino]-butan-2-ol

¹H NMR (METHANOL-d₄) δ 8.71-8.66 (m, 2H), 8.25-8.61 (m, 1H), 8.24-7.84(m, 3H), 4.24-4.22 (m, 1H), 1.31-1.28 (s, 3H). LC-MS: m/z 488.0 (M+H)⁺.

Compound 592N-tert-Butyl-N′-(3-fluoro-5-methanesulfonyl-phenyl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.75-8.73 (m, 1H), 8.24-8.21 (m, 2H), 7.99-7.92(m, 2H), 7.39-7.37 (m, 1H), 3.20 (s, 3H), 1.57 (s, 9H). LC-MS: m/z 485.1(M+H)⁺.

Compound 593N-Cyclopropylmethyl-N′-(3-fluoro-5-methanesulfonyl-phenyl)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.60 (m, 2H), 8.22-7.95 (m, 3H), 7.34-7.33(m, 1H), 3.44-3.39 (m, 2H), 3.20 (s, 3H), 1.23 (m, 1H), 0.36-0.10 (m,2H). LC-MS: m/z 483.1 (M+H)⁺.

Compound 5941-((4-(6-(1,1-difluoroethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.61-8.21 (m, 3H), 8.15-7.85 (m, 3H), 3.59 (d,2H), 2.11 (t, 3H), 1.27 (d, 6H). LC-MS: m/z 470.2 (M+H)⁺.

Compound 595N2-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.66-8.28 (m, 3H), 8.22-7.85 (m, 3H), 3.42 (dd,2H), 2.11 (t, 3H), 1.21 (br, 1H), 0.59-0.55 (m, 2H), 0.36-0.31 (m, 2H).LC-MS: m/z 452.2 (M+H)⁺.

Compound 596N2-(tert-butyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(2-(1,1-difluoroethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.55-8.41 (m, 3H), 8.11-8.07 (m, 1H), 7.86-7.76(m, 2H), 2.14-1.93 (m, 6H), 1.56 (s, 9H). LC-MS: m/z 450.2 (M+H)⁺.

Compound 597N2-(cyclopropylmethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.75-8.73 (d, 2H), 8.55-8.38 (m, 1H), 8.28-8.22(m, 1H), 8.02 (d, 1H), 7.88 (br, 1H), 3.53-3.41 (dd, 2H), 1.21 (br, 1H),0.64-0.58 (m, 2H), 0.46-0.33 (m, 2H). LC-MS: m/z 456.2 (M+H)⁺.

Compound 598N2-(cyclopropylmethyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.68-865 (m, 1H), 8.22-8.18 (m, 1H), 7.97-7.95(m, 1H), 7.56-7.52 (m, 2H), 6.61-6.56 (m, 1H), 3.44-3.38 (m, 2H),1.20-1.18 (m, 1H), 0.57-0.55 (m, 2H), 0.34-0.33 (m, 2H). LC-MS: m/z423.2 (M+H)⁺.

Compound 599N2-(3-chloro-5-(methylsulfonyl)phenyl)-N4-(cyclopropylmethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.73-8.71 (m, 2H), 8.24-8.20 (t, J=8 Hz, 1H),8.10 (s, 1H), 7.99-7.97 (d, J=8 Hz, 1H), 7.61 (s, 1H), 3.49-3.43 (m,2H), 3.19 (s, 1H), 1.23-1.19 (m, 1H), 0.58-0.55 (m, 2H), 0.39-0.35 (m,2H). LC-MS: m/z 499.2 (M+H)⁺.

Compound 600N2-(tert-butyl)-N4-(3-chloro-5-(methylsulfonyl)phenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.68-8.66 (m, 2H), 8.43-8.28 (m, 1H), 8.18-8.14(m, 2H), 7.94-7.92 (d, J=7.6 Hz, 1H), 7.58-7.53 (m, 1H), 3.16 (s, 3H),1.53 (s, 9H). LC-MS: m/z 501.2 (M+H)⁺.

Compound 601N2-(tert-butyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.64-8.62 (m, 1H), 8.20-8.16 (m, 1H), 7.95-7.93(m, 1H), 7.50-7.48 (m, 2H), 6.60-6.53 (m, 1H), 1.53 (s, 9H). LC-MS: m/z425.5 (M+H)⁺.

Compound 602N2-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67-8.64 (m, 1H), 8.49-8.48 (m, 1H), 8.21-8.17(m., 2H), 7.96-7.94 (m, 1H), 7.81 (br.s., 1H), 1.55 (s, 9H). LC-MS: m/z458.2 (M+H)⁺.

Compound 603N2-(3,5-difluorophenyl)-N4-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.35-8.16 (d, 1H), 7.79-7.65 (m, 1H), 7.58-7.56(s, 2H), 7.30-7.20 (d, 1H), 6.10-6.0 (s, 1H), 4.50-4.27 (m, 1H),1.33-1.31 (d, 6H). LC-MS: m/z 411.1 (M+H)⁺.

Compound 604N2-(cyclopropylmethyl)-N4-(2-(1,1-difluoroethyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.68 (d, 1H), 8.50-8.18 (m, 3H), 8.02-7.73 (m,2H), 3.42 (dd, 2H), 2.01 (t, 2H), 1.24-1.16 (m, 1H), 0.58-0.55 (m, 2H),0.35-0.33 (m, 2H). LC-MS: m/z 452.1 (M+H)⁺.

Compound 6051-((4-(6-(1,1-difluoroethyl)pyridin-2-yl)-6-((2-(1,1-difluoroethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.58-8.13 (m 3H), 8.11-7.76 (m, 3H), 3.60 (d,2H), 2.17-1.93 (m, 6H), 1.28 (d, 6H). LC-MS: m/z 466.1 (M+H)⁺.

Compound 6061-(4-((4-(tert-butylamino)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.71-8.5 (m, 1H), 8.4-8.2 (m, 1H), 8.1 (m, 1H),7.9 (m, H), 7.6 (m, 1H), 2.15-2.06 (t, J=18 Hz, 3H), 1.78-1.74 (d, J=16Hz, 4H), 1.55 (s, 9H). LC-MS: m/z 450.2 (M+H)⁺.

Compound 607N2-(cyclopropylmethyl)-N4-(3-(methylsulfonyl)phenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO, T=273+80K) δ 10.03 (s, 1H), 8.78 (s, 1H), 8.59-8.57 (m,1H), 8.28-8.24 (m, 1H), 8.04-7.97 (m, 2H), 7.59-7.84 (m, 3H), 3.35(br.s., 2H), 3.17 (S, 3H), 1.15-1.14 (m, 1H), 0.48-0.46 (m, 2H),0.32-0.31 (m, 2H). LC-MS: m/z 465.2 (M+H)⁺.

Compound 6081-(4-((4-(tert-butylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.87-8.85 (m, 1H), 8.7-8.11 (m, 2H), 7.96-7.87(m, 1H), 7.585-7.583 (m, 1H) 1.8-1.70 (d, 4H), 1.59-1.54 (m, 6H). LC-MS:m/z 455.1 (M+H)⁺.

Compound 609N2-(3-chloro-5-(methylsulfonyl)phenyl)-N4-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.65 (s, 1H), 8.54-8.51 (m, 1H), 8.06-8.04 (t,J=7.8 Hz, 2H), 7.84-7.82 (d, J=7.6 Hz, 1H), 7.57-7.56 (m, 1H), 3.39-3.37(m, 2H), 3.14 (s, 3H), 2.13-20.3 (t, J=19.2 Hz, 1H), 1.18-1.13 (m, 1H),0.54-0.50 (m, 2H), 0.32-0.31 (m, 2H). LC-MS: m/z 501.2 (M+H)⁺.

Compound 610N2-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(2-(1,1-difluoroethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.56-8.13 (m, 3H), 8.11-7.77 (m, 3H), 3.45-3.40(m, 2H), 2.15-1.94 (m, 6H), 1.22-1.18 (m, 1H), 0.58-1.19 (m, 1H),0.59-0.54 (m, 2H), 0.36-0.31 (m, 2H). LC-MS: m/z 448.2 (M+H)⁺.

Compound 611N2-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.96 (s, 1H), 8.58-8.55 (m, 1H), 8.10-7.78 (m,3H), 7.62-7.55 (m, 2H), 3.44-3.41 (m, 2H), 3.14 (d, 3H), 2.11 (t, 3H),1.20-1.17 (m, 1H), 0.57-0.52 (m, 2H), 0.36-0.33 (m, 2H). LC-MS: m/z461.2 (M+H)⁺.

Compound 612N2-(cyclopropylmethyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(3-fluoro-5-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.58-8.13 (m, 2H), 8.12-7.86 (m, 2H), 7.36-7.32(m, 1H), 3.46-3.41 (m, 2H), 3.19 (d, 3H), 2.13 (t, 3H), 1.24-1.18 (m,1H), 0.59-0.56 (m, 2H), 0.37-0.35 (m, 2H). LC-MS: m/z 479.2 (M+H)⁺.

Compound 6136-(6-(1,1-difluoroethyl)pyridin-2-yl)-N2-(3-fluoro-5-(methylsulfonyl)phenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.57 (d, 2H), 8.13-7.86 (m, 3H), 7.37-7.32 (m,1H), 4.37-4.34 (m, 1H), 3.19 (d, 3H), 2.18-2.06 (m, 3H), 1.35-1.32 (m,6H). LC-MS: m/z 467.2 (M+H)⁺.

Compound 614N2-(3-chloro-5-(methylsulfonyl)phenyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.73-8.33 (m, 2H), 8.11 (t, 2H), 7.87 (d, 1H),7.61 (s, 1H), 4.48-4.28 (m, 1H), 3.20 (d, 3H), 2.13 (t, 3H), 1.34 (t,6H). LC-MS: m/z 488.2 (M+H)⁺.

Compound 615N2-(tert-butyl)-N4-(3-chloro-5-(methylsulfonyl)phenyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.57-8.56 (m, 1H), 8.43-8.25 (m, 2H), 8.12-8.06(m, 1H), 7.85 (d, 1H), 7.61 (s, 1H), 3.17 (s, 3H), 2.11 (t, 3H), 1.56(s, 9H). LC-MS: m/z 497.2 (M+H)⁺.

Compound 616N2-(tert-butyl)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-N4-(3-fluoro-5-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.59-8.42, 8.13-8.05 (m, 2H), 7.87 (d, 1H),7.39-7.34 (m, 1H), 3.19 (s, 3H), 2.18-2.06 (m, 3H), 1.57 (s, 9H). LC-MS:m/z 481.2 (M+H)⁺.

Compound 6171-(4-((4-((cyclopropylmethyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.87-8.85 (m, 1H), 8.7-8.11 (m, 2H), 7.96-7.87(m, 1H), 7.585-7.583 (m, 1H), 3.35 (br.s., 2H), 1.15-1.14 (m, 1H),0.48-0.46 (m, 2H), 0.32-0.31 (m, 2H). LC-MS: m/z 453.1 (M+H)⁺.

Compound 618(4-((4-((cyclopropylmethyl)amino)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)-2-methylpropanenitrile

¹H NMR (METHANOL-d₄) δ 8.60-8.56 (m, 1H), 8.44-8.37 (m, 2H), 8.11-8.03(m, 1H), 7.87-7.85 (m, 1H), 7.62-7.60 (m, 1H), 3.45-3.43 (d, 2H),2.15-2.06 (t, 3H), 1.78 (s, 6H), 1.21-1.16 (m, 1H), 0.57-0.54 (m, 2H),0.36-0.33 (m, 2H). LC-MS: m/z 451.2 (M+H)⁺.

Compound 6191-(4-((4-((cyclopropylmethyl)amino)-6-(6-(1,1-difluoroethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.64-8.57 (t, 1H), 8.54-8.53 (d, 1H), 8.26-8.25(d, 1H), 8.09-8.05 (m, 1H), 7.86-7.83 (m, 1H), 7.45-7.42 (m, 1H),3.46-3.44 (d, 2H), 2.16-2.06 (q, 3H), 1.80-1.71 (m, 4H), 1.19-1.12 (m,1H), 0.56-0.53 (m, 2H), 0.37-0.34 (m, 2H). LC-MS: m/z 449.3 (M+H)⁺.

N2-isopropyl-6-(6-(2,2,2-trifluoroethylamino)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₄): δ 10.6-10.2 (m, 1H), 8.7-8.4 (m, 2H), 8.4-7.8 (m, 2H),7.8-7.5 (m, 2H), 7.4-7.2 (m, 1H), 6.8 (m, 1H), 4.5-4.0 (m, 3H), 1.2 (d,J=4.8 Hz, 1H). LC-MS: m/z 473.2 (M+H)⁺.

The following compounds were prepared according to the general procedureshown in Scheme 4:

The following intermediates prepared according to Example 4, step 1,using appropriate reagents:

Preparation of (4,6-Dichloro-[1,3,5]triazin-2-yl)-oxetan-3-yl-amine

Using the standard procedure described above yielded the title compoundwhich was directly used in the next step.

Preparation of(4,6-Dichloro-[1,3,5]triazin-2-yl)-(3-oxa-bicyclo[3.1.0]hex-6-yl)-amine

Using the standard procedure described above except DIPEA (1 eq) wasadded to give(4,6-Dichloro-[1,3,5]triazin-2-yl)-(3-oxa-bicyclo[3.1.0]hex-6-yl-amineas a white solid.

LCMS: m/z 247.1 (M+H)⁺.

The following intermediates were prepared according to Example 4, step2: Preparation of4-chloro-6-(2-fluoro-3-methoxyphenyl)-N-(oxetan-3-yl)-1,3,5-triazin-2-amineUsing the standard procedure described above yielded the title compound.

LCMS: m/z 311.0 (M+H)⁺.

Step 2-9: Preparation of4-chloro-6-(2-fluoro-5-methoxyphenyl)-N-(oxetan-3-yl)-1,3,5-triazin-2-amine

Using the standard procedure described above yielded the title compound.

LCMS: m/z 311.1 (M+H)⁺.

Preparation ofN-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-chloro-6-(2-fluorophenyl)-1,3,5-triazin-2-amine

Using the standard procedure described above yielded the title compound

LCMS: m/z 306.9 (M+H)⁺.

Preparation of4-chloro-6-(2-fluorophenyl)-N-isobutyl-1,3,5-triazin-2-amine

Using the standard procedure described yielded the title compound

LCMS: m/z 281.1 (M+H)⁺.

Preparation of4-Chloro-6-(6-fluoro-5-methoxyphenyl)-N-isopropyl-1,3,5-tri-azin-2-amine

Using the standard procedure described above yielded the title compoundas a white solid.

LCMS: m/z 297.1 (M+H)⁺.

Preparation of4-(3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-6-chloro-N-isopropyl-1,3,5-triazin-2-amine

Using the standard procedure described above yielded the title compoundas a colorless oil.

The following compounds were synthesized using Example 4, step 3(Procedure C), utilizing appropriate intermediates and reagents:

Compound 6211-(4-(2-fluorophenyl)-6-(5-fluoropyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.68-9.01 (m, 1H), 8.44-8.51 (m, 2H), 8.20-8.23(m, 1H), 8.76-8.77 (m, 1H), 7.38-7.47 (m, 2H), 7.76-7.81 (m, 2H),3.56-3.61 (m, 2H), 1.27-1.31 (m, 6H). LC-MS: m/z 373.3 (M+H)⁺.

Compound 6221-(4-(2-fluorophenyl)-6-(6-fluoropyridin-3-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.08-8.15 (m, 1H), 7.96-7.97 (m, 2H), 7.83-7.89(m, 1H), 7.51-7.54 (m, 2H), 7.21-7.31 (m, 2H), 3.53-3.55 (m, 2H),3.56-3.61 (m, 2H), 1.25-1.27 (m, 6H). LC-MS: m/z 373.2 (M+H)⁺.

Compound 6231-(4-(2-fluorophenyl)-6-(2-fluoropyridin-4-ylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

¹H NMR (METHANOL-d₄) δ 8.27-8.55 (m, 1H), 8.25-8.27 (m, 2H), 7.77-7.78(m, 1H), 7.39-7.47 (m, 2H), 7.16-7.19 (m, 1H), 3.51-3.53 (m, 2H), 1.28(m, 6H). LC-MS: m/z 373.2 (M+H)⁺.

Compound 6246-(2-Fluoro-3-methoxy-phenyl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.53-10.43 (m, 1H), 8.89-7.92 (m, 4H), 7.55-7.48 (m,1H), 7.39-7.34 (m, 1H), 7.25 (t, J=8.25 Hz, 1H), 5.07-5.01 (m, 1H),4.83-4.77 (m, 2H), 4.61 (t, J=6.18 Hz, 2H), 3.88 (s, 3H). LC-MS: m/z437.2 (M+H)⁺.

Compound 6256-(2-Fluoro-phenyl)-N-(5-fluoro-pyridin-3-yl)-N′-oxetan-3-yl-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.17-10.12 (m, 1H), 8.77-7.98 (m, 5H), 7.61-7.59 (m,1H), 7.37-7.34 (m., 2H), 5.09-5.06 (m, 1H), 4.81-4.80 (m, 2H), 4.62-4.61(m, 2H). LC-MS: m/z 357.1 (M+H)⁺.

Compound 6266-(2-Fluoro-phenyl)-N-(6-fluoro-pyridin-3-yl)-N′-oxetan-3-yl-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d6) δ 10.06-9.59 (m, 1H), 8.71-8.29 (m, 3H), 8.07-7.95 (m,1H), 7.61-7.56 (m., 1H), 7.34-7.28 (m, 2H), 7.16-7.15 (m, 1H), 5.06-4.95(m, 1H), 4.77-4.76 (m, 2H), 4.59-4.56 (m, 2H). LC-MS: m/z 357.1 (M+H)⁺.

Compound 6276-(2-Fluoro-phenyl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.56-8.47 (m, 2H), 8.17-7.89 (m, 2H), 7.58-7.53(m, 1H), 7.31-7.21 (m., 2H), 5.34-5.24 (m, 1H), 5.01-4.99 (m, 2H),4.80-4.73 (m, 2H). LC-MS: m/z 407.2 (M+H)⁺.

Compound 6286-(2-Fluoro-phenyl)-N-(2-fluoro-pyridin-4-yl)-N′-oxetan-3-yl-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d6) δ 10.45-10.39 (m, 1H), 8.86-8.68 (m, 1H), 8.08-7.69 (m,5H), 7.37-7.33 (m., 2H), 5.11-5.09 (m, 1H), 4.85-4.80 (m, 2H), 4.64-4.59(m, 2H). LC-MS: m/z 357.1 (M+H)⁺.

Compound 6296-(2-Fluoro-phenyl)-N-oxetan-3-yl-N′-(5-trifluoromethyl-pyridin-3-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.34-10.20 (m, 1H), 9.25-8.50 (m, 3H), 8.06-8.00 (m,1H), 7.77-7.72 (m., 1H), 7.39-7.25 (m, 2H), 5.10-4.99 (m, 1H), 4.79-4.56(m, 2H), 4.59-4.52 (m, 2H). LC-MS: m/z 407.3 (M+H)⁺.

Compound 6306-(2-Fluoro-5-methoxy-phenyl)-N-isopropyl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.70-7.82 (m, 3H), 7.67-7.61 (m, 1H), 7.16-7.06(m, 2H), 4.30-4.25 (m., 1H), 3.84 (s, 3H), 4.26-4.23 (m, 1H),1.317-1.279 (d, J=15.2 MHz, 3H). LC-MS: m/z 422.9 (M+H)⁺.

Compound 6316-(2-Fluoro-3-methoxy-phenyl)-N-isopropyl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.65-7.83 (m, 3H), 7.59-7.56 (m, 1H), 7.24-7.16(m, 2H), 4.28-4.25 (m., 1H), 3.92 (s, 3H), 1.315-1.272 (d, J=17.2 MHz,3H). LC-MS: m/z 423.0 (M+H)⁺.

Compound 6322-(4-((4-(2-fluorophenyl)-6-(isopropylamino)-1,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol

¹H NMR (DMSO-d₆) δ 8.30-8.08 (m, 3H), 7.70-7.51 (m, 2H), 7.29 (t, 1H),7.24-7.19 (dd, 1H), 4.36-4.34 (m, 1H), 1.57 (s, 6H), 1.32-1.28 (m, 6H).LC-MS: m/z 383.3 (M+H)⁺.

Compound 6332-Fluoro-3-[4-isopropylamino-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenol

¹H NMR (METHANOL-d₄) δ 8.70-8.68 (d, J=6 Hz, 1H), 8.56-8.49 (m, 1H),7.90-7.89 (m, 1H), 7.59-7.57 (m., 1H), 7.33-7.23 (m, 2H), 4.39-4.35 (m,1H), 1.407-1.391 (d, J=6.4 Hz, 3H). LC-MS: m/z 409.3 (M+H)⁺.

Compound 6344-Fluoro-3-[4-isopropylamino-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenol

¹H NMR (METHANOL-d₄) δ 8.70-8.68 (d, J=5.6 MHz, 1H), 8.56-8.53 (m, 1H),7.91-7.89 (m, 1H), 7.58-7.55 (m., 1H), 7.27-7.15 (m, 2H), 4.40-4.35 (m,1H), 1.40-1.39 (d, J=6.4 MHz, 3H). LC-MS: m/z 409.1 (M+H)⁺.

Compound 6356-(2-Fluoro-5-methoxy-phenyl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.73-10.63 (m, 1H), 9.11-8.11 (m, 4H), 7.82-7.69 (m,1H), 7.47 (t, J=9.62 Hz, 1H), 7.35 (brs., 1H), 5.34-5.20 (m, 1H),5.04-5.00 (m, 2H), 4.83-4.80 (m, 2H), 3.80 (s, 3H). LC-MS: m/z 437.3(M+H)⁺

Compound 6366-(2-Fluoro-phenyl)-N-(2-fluoro-pyridin-4-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.50-10.21 (m, 1H), 8.35-7.85 (m, 4H), 7.62-7.52 (m,2H), 7.37-7.29 (m, 2H), 3.96-3.88 (m., 2H), 3.69-3.61 (m, 2H), 2.66-2.49(m, 1H), 1.94-1.87 (m, 2H). LC-MS: m/z 383.1 (M+H)⁺.

Compound 6376-(2-Fluoro-phenyl)-N-(6-fluoro-pyridin-3-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.71-8.57 (m, 1H), 8.30 (brs. 1H), 8.18 (brs.1H), 7.81 (brs. 1H), 7.50-7.43 (m., 2H), 7.21 (brs. 1H), 4.12-4.02 (m,2H), 3.81-3.75 (m, 2H), 2.80-2.68 (m, 1H), 2.14-2.09 (m, 2H). LC-MS: m/z383.2 (M+H)⁺.

Compound 6386-(2-Fluoro-phenyl)-N-(5-fluoro-pyridin-3-yl)-N′-(3-oxa-bicyclo[3.1.0]hex-6-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.67 (brs., 2H), 8.20-8.07 (m, 2H), 7.56 (brs.,1H), 7.32-7.21 (m, 2H), 4.14-4.05 (m., 2H), 3.83-3.78 (m, 2H), 2.71-2.68(m, 1H), 2.00-1.96 (m, 2H). LC-MS: m/z 383.1 (M+H)⁺.

Compound 639{3-[4-Isopropylamino-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenyl}-methanol

¹H NMR (METHANOL-d₄) δ 8.37-8.41 (m, 3H), 8.31-8.28 (m, 2H), 7.53-7.53(d, J=6 Hz, 1H), 7.46-7.45 (m, 1H), 4.685 (s, 2H), 4.52-4.18 (m, 1H),1.31-1.30 (d, J=6.4 Hz, 6H). LC-MS: m/z 405.1 (M+H)⁺.

Compound 6403-[4-Isopropylamino-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenol

¹H NMR (METHANOL-d₄) δ 8.679-8.245 (m, 2H), 7.95-7.83 (m, 2H),7.32-7.282 (m, 1H), 7.00-6.98 (d, J=8 Hz, 1H), 4.31-4.28 (m, 1H),1.34-1.25 (m, 6H). LC-MS: m/z 391.2 (M+H)⁺.

Compound 6413-(4-((2-hydroxy-2-methylpropyl)amino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenol

¹H NMR (METHANOL-d₄) δ 8.72-8.70 (m, 1H), 8.68-8.38 (m, 1H), 8.28-7.96(m, 1H), 7.79-7.70 (m, 2H), 7.51-7.44 (m, 1H), 7.23-7.17 (m, 1H), 3.65(d, 2H), 1.36 (d, 6H). LC-MS: m/z 421.2 (M+H)⁺.

Compound 6425-(4-((3,5-difluorophenyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)benzene-1,3-diol

¹H NMR (METHANOL-d₄) δ 7.51-7.48 (m, 2H), 7.30 (d, 2H), 6.52-6.41 (m,2H), 4.23-4.21 (m, 1H), 1.35-1.27 (m, 6H). LC-MS: m/z 374.1 (M+H)⁺.

Compound 6446-(3-Chloro-5-trifluoromethyl-phenyl)-N-isopropyl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.79-8.50 (m, 3H), 8.49-7.86 (m, 2H), 7.77-7.76(m, 1H), 4.26-4.23 (m, 1H), 1.32-1.30 (d, 6H). LC-MS: m/z 477.1 (M+H)⁺.

Compound 6456-(6-aminopyridin-3-yl)-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 9.80 (d, 1H), 8.87 (d, 1H), 8.52-7.29 (m, 5H),6.78-6.50 (m, 3H), 4.29-4.11 (m, 1H), 1.20 (d, 6H). LC-MS: m/z 358.2(M+H)⁺.

Compound 6463-(4-(tert-butylamino)-6-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-1,3,5-triazin-2-yl)phenol

¹H NMR (METHANOL-d₄) δ 8.37-7.74 (m, 4H), 7.25 (br, 2H), 6.92 (br, 1H),3.13 (s, 3H), 1.51 (s, 6H). LC-MS: m/z 432.0 (M+H)⁺.

Compound 6476-(3-chloro-5-fluorophenyl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

1H NMR (DMSO-d₆) δ 10.39-10.56 (m, 1H), 8.16-8.70 (m, 4H), 7.71-8.00 (m,3H), 4.16-4.35 (m, 1H), 1.25 (dd, J=6.4, 6H). LC-MS: m/z 427.1 (M+H)⁺.

Compound 648N2-isopropyl-6-(2-methoxypyridin-3-yl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.61-8.27 (m, 3H), 8.23-7.88 (m, 2H), 7.09-7.06(m, 1H), 4.28-4.25 (m, 1H), 4.01 (s, 3H), 1.31-1.28 (m, 6H). LC-MS: m/z406.1 (M+H)⁺.

Example 9 Preparation of Compounds of Formula I Wherein Ring A isSubstituted Aryl or Heteroaryl

The compounds of this Example are prepared by the general method inScheme 9, set forth below.

Compound 6496-(2-aminopyrimidin-5-yl)-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

Example 9, Step 1 Preparation of6-chloro-N²-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

To a solution of 4,6-dichloro-N-isopropyl-1,3,5-triazin-2-amine (1 g,4.83 mmol) in THF (10 mL) was added 3,5-difluoro aniline (0.62 g, 4.83mmol), ^(t)BuONa (0.93 g, 9.66 mol) and Pd(dppf)Cl₂ (0.35 g, 0.48 mmol).The mixture was stirred at 80° C. under N2 protection from 2 hrs. Thereaction was quenched by water and extracted by EtOAc. The organic layerwas dried, concentrated and purified to afford6-chloro-N2-(3,5-difluorophenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamineas white solid.

Example 9, Step 2

To a mixture of5-chloro-N1-(3,5-difluorophenyl)-N3-isopropylbenzene-1,3-diamine (50 mg,0.17 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (37 mg,0.17 mmol) and Cs₂CO₃ (108 mg, 0.34 mmol) in dioxane/water (0.8 mL/0.16mL) was added Pd(PPh₃)₄ (19 mg, 0.017 mmol). The mixture was heated to80° C. for 2 hours. The mixture was concentrated and purified by astandard method to give6-(2-aminopyrimidin-5-yl)-N2-(3,5-difluoro-phenyl)-N4-isopropyl-1,3,5-triazine-2,4-diamine.

¹H NMR (METHANOL-d4): δ 9.11-9.17 (m, 2H), 7.49-7.50 (m, 2H), 6.51-6.55(m, 1H), 4.22-4.34 (m, 1H), 1.35 (d, J=6.8 Hz, 6H). LC-MS: m/z 359.2(M+H)⁺.

The following compounds were prepared according Example 8, method B,using appropriate intermediates and reagents.

Compound 6506-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)pyridin-2(1H)-one

¹H NMR (METHANOL-d₄) δ 8.70-8.25 (m, 2H), 8.15-8.06 (m, 1H), 7.81-7.50(m, 1H), 6.89 (br, 1H), 4.31-4.23 (m, 1H), 1.34-1.29 (m, 6H). LC-MS: m/z392.1 (M+H)⁺.

Compound 6516-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)picolinamide

¹H NMR (DMSO-d₆) δ 10.56 (br, 1H), 8.87-8.85 (m, 1H), 8.68-8.04 (m, 6H),7.92-7.96 (m, 1H), 7.63-7.59 (m, 1H), 7.58-7.48 (m, 1H), 4.20-4.15 (m,1H), 1.25 (d, 6H). LC-MS: m/z 418.2 (M+H)⁺.

Compound 6522,2,2-trifluoro-1-(3-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenyl)ethanol

¹H NMR (METHANOL-d₄) δ 8.76-8.40 (m, 4H), 8.32-7.52 (m, 3H), 5.16-5.11(m, 1H), 4.51-4.28 (m, 1H), 1.34 (d, 6H). LC-MS: m/z 473.2 (M+H)⁺.

Compound 653N-Isopropyl-6-(3-methanesulfinyl-phenyl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.81-8.28 (m, 4H), 7.91-7.71 (m, 3H), 4.51-4.28(m, 1H), 2.88 (s, 3H), 1.36-1.33 (m, 6H). LC-MS: m/z 437.2 (M+H)⁺.

Compound 6546-(3-(aminomethyl)phenyl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d4) δ 8.66-8.40 (m, 4H), 7.96 (br, 1H), 7.77-7.67 (m,2H), 4.52-4.31 (m, 1H), 4.24 (s, 2H), 1.34 (d, 6H). LC-MS: m/z 404.2(M+H)⁺.

Compound 6556-(3-chloro-5-methoxyphenyl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.44 (d, 1H), 8.71 (s, 1H), 8.57-8.55 (m, 1H),8.30-8.08 (m, 1H), 7.92-7.79 (m, 3H), 6.97 (s, 1H), 4.35-4.13 (m, 1H),3.86 (s, 3H), 1.24 (d, 6H). LC-MS: m/z 439.2 (M+H)⁺.

Compound 657N-Isopropyl-6-(3-methanesulfonyl-phenyl)-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine

¹H NMR (METHANOL-d₄) δ 8.95 (s, 1H), 8.76-7.98 (m, 5H), 7.80-7.76 (m,1H), 4.49-4.22 (m, 1H), 3.17 (s, 3H), 1.34-1.27 (m, 6H). LC-MS: m/z453.2 (M+H)⁺.

Compound 6583-Fluoro-5-[4-isopropylamino-6-(2-trifluoromethyl-pyridin-4-ylamino)-[1,3,5]triazin-2-yl]-phenol

¹H NMR (METHANOL-d₄) δ 8.63-8.63 (m, 2H), 7.95 (s, 1H), 7.56-7.49 (m,2H), 6.80-6.78 (d, J=8.8 Hz, 1H), 4.31 (s, 1H), 1.36-1.34 (d, J=6 Hz,6H). LC-MS: m/z 409.1 (M+H)⁺.

Compound 6606-(3-fluoro-5-(trifluoromethyl)phenyl)-N2-isopropyl-N4-(3-(methylsulfonyl)phenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (Methanol-d₄) δ 8.98 (s, 1H), 8.55 (s, 1H), 8.37 (d, 1H),7.99-7.75 (m, 1H), 7.61-7.53 (m, 3H), 4.37-4.34 (m, 1H), 3.15 (d, 3H),1.30 (d, 6H). LC-MS: m/z 470.0 (M+H)⁺.

Compound 6626-(3-fluoro-5-methoxyphenyl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (DMSO-d₆) δ 10.30 (d, 1H), 8.67-8.04 (m, 3H), 8.04-7.58 (m, 3H),7.08-7.03 (m, 1H), 4.35-4.10 (m, 1H), 3.83 (s, 3H), 1.21 (d, 3H). LC-MS:m/z 423.2 (M+H)⁺.

Compound 6631-(3-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenyl)ethanol

¹H NMR (METHANOL-d₄) δ 8.74-8.29 (m, 4H), 8.28-7.80 (m, 1H), 7.57-7.43(m, 2H), 4.48-4.26 (m, 1H), 1.49 (d, 3H), 1.31 (d, 6H). LC-MS: m/z 419.2(M+H)⁺.

6-(3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-N2-isopropyl-N⁴-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

LCMS: m/z 545.3 (M+H)⁺.

To a solution of 6-(3-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine(510 mg, 0.936 mmol) in anhydrous THF (15 mL) was TBAF (490 mg, 1.872mmol) at room temperature. The mixture was stirred at r.t. for 2 hours.The mixture was partitioned between EtOAc and water. The organic layerwas washed with brine, dried over Na₂SO₄, then concentrated. The crudeproduct was purified by a standard method to give1-(3-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenyl)cyclopropanol.

Compound 6641-(3-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenyl)cyclopropanol

¹H NMR (METHANOL-d₄) δ 8.67-8.46 (m, 2H), 8.31-8.21 (m, 2H), 7.84-7.83(m, 1H), 7.52-7.39 (m, 2H), 4.45-4.23 (m, 1H), 1.32-1.30 (d, J=8.0 Hz,6H), 1.23-1.22 (m, 2H), 1.09-1.06 (m, 2H). LC-MS: m/z 431.2 (M+H)⁺.

Compound 6653-(hydroxymethyl)-5-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)phenol

¹H NMR (CDCl₃) δ 10.40-10.24 (m, 1H), 9.56 (s, 1H), 8.68-8.26 (m, 2H),7.93-7.59 (m, 3H), 6.94 (s, 1H), 5.23-5.20 (m, 1H), 4.50-4.49 (d, J=5.6,2H), 4.20-4.12 (m, 1H) 1.26-1.23 (m, 6H). LC-MS: m/z 421.2 (M+H)⁺.

The following compounds were prepared according to Scheme 5 usingappropriate intermediates and reagents:

Compound 6674-(4-Phenyl-6-phenylamino-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

¹H NMR (CDCl3) δ: 8.23-8.82 (m, 2H), 8.53-7.66 (m., 2H), 7.33-7.48 (m,3H), 7.25-7.31 (m, 2H), 6.98-7.09 (m., 2H), 5.05-5.29 (m, 1H), 3.95-4.20(m, 3H), 2.85-2.97 (m, 2H), 2.03 (d, J=12 Hz, 2H), 1.37-1.42 (m, 11H).LC-MS: m/z 447.0 (M+H)⁺.

Example 10 Preparation of Compounds of Formula 1 Via N-Arylation ofTriazine-Amine Cross-Coupling

Example 10, Step 1 Preparation ofN2-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine

To the solution of4-chloro-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine(300 mg, 0.94 mmol) in THF (5 mL) was added NH_(3/)H₂O (8 mL). Themixture was stirred at 80° C. overnight. TLC (PE: EA=1:1) showed thereaction was complete. The mixture was washed with H₂O and ethylacetate. The organic layer was dried over Na₂SO₄, filtered, concentratedto giveN2-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamineas a yellow solid which was used without further purification. LC-MS:m/z 299.8 (M+H)⁺.

The following intermediates were prepared using the procedure in Example10, Step 1:

6-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-N-isopropyl-[1,3,5]triazine-2,4-diamine

LC-MS: m/z 295.2 (M+H)⁺.

6-(6-Difluoromethyl-pyridin-2-yl)-N-isopropyl-[1,3,5]triazine-2,4-diamine

LC-MS: m/z 281.1 (M+H)⁺.

1-(4-amino-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

LC-MS: m/z 329.0 (M+H)⁺.

Step 2: Preparation of1-(4-(4-(isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-ylamino)pyridin-2-yl)cyclopropanecarbonitrile

To a solution ofN2-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diamine(120 mg, 0.4 mmol) in anhydrous toluene (5 mL) was added1-(4-chloro-pyridin-2-yl)cyclopropanecarbonitrile (89 mg, 0.48 mmol),Cs₂CO₃ (262 mg, 0.8 mmol), BINAP (24.9 mg, 0.04 mmol), and Pd₂(dba)₃(36.6 mg, 0.04 mmol) under N₂. The mixture was stirred at 110° C. for 30min under M.W. irradiation. The mixture was quenched by water andextracted with ethyl acetate. The organic layer was dried with anhydrousNa₂SO₄, concentrated and purified by a standard method to give1-(4-(4-(isopropylamino)-6-(6-(trifluoromethyl)-pyridin-2-yl)-1,3,5-triazin-2-ylamino)pyridin-2-yl)cyclopropanecarbonitrile.The following compounds were prepared from the appropriate intermediatesusing the procedure in Example 10, Step 2:

Compound 6691-{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-cyclopropanecarbonitrile

¹H NMR (METHANOL-d₄) δ 8.79-8.78 (m, 2H), 8.27 (d, J=5.6 Hz, 1H), 8.20(t, J=8.2 Hz, 1H), 7.36 (dd, J=3.6 Hz, 2.0 Hz, 1H), 4.47 (m, 1H),1.82-1.73 (m, 4H), 1.31 (d, J=4.0 Hz, 6H). LC-MS: m/z 441.2 (M+H)⁺.

Compound 6701-[4-(5-Chloro-6-fluoro-pyridin-3-ylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-2-methyl-propan-2-ol

Using the standard procedure described in except replacing BINAP withX-Phos and Cs₂CO₃ with t-BuONa to give 670.

¹H NMR (METHANOL-d₄) δ 8.82-8.63 (m, 2H), 8.39-8.38 (m, 1H), 8.22 (t,J=7.9 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 3.63 (s, 1H), 3.55 (s, 1H), 1.30(d, J=4.0 Hz, 6H). LC-MS: m/z 458.2 (M+H)⁺.

Compound 6712-{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-2-methyl-propionitrile

¹H NMR (METHANOL-d₄) δ 8.77-8.73 (m, 1H), 8.50 (s, 1H), 8.40 (d, J=4.4Hz, 1H), 8.23 (t, J=6.6 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.57 (dd, J=3.6Hz, 2.0 Hz, 1H), 4.49-4.41 (m, 1H), 1.74 (s, 6H), 1.34 (d, J=6.4 Hz,6H). LC-MS: m/z 443.2 (M+H)⁺.

Compound 672{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-acetonitrile

¹H NMR (METHANOL-d₄) δ 10.41 (s, 1H), 8.62 (dd, J=9.6 Hz, 8.0 Hz, 1H),8.37 (d, J=2.4 Hz, 1H), 8.29 (dd, J=8.4 Hz, 1.9 Hz, 2H), 8.28 (s, 1H),8.11 (d, J=7.6 Hz, 1H), 7.97-7.67 (m, 1H), 4.35-4.28 (m, 1H), 4.17 (s,1H), 4.13 (s, 1H), 1.25 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.3 (M+H)⁺.

Compound 6736-(6-Difluoromethyl-pyridin-2-yl)-N-(2-difluoromethyl-pyridin-4-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

Using the standard procedure described in Example 10 Step 2 exceptreplacing Cs₂CO₃ by t-BuONa yielded 673.

¹H NMR (METHANOL-d₄) δ 8.64-7.77 (m, 6H), 6.98-6.58 (m, 2H), 4.33-4.30(m, 1H), 1.34 (d, J=6.4 Hz, 6H). LC-MS: m/z 408.2 (M+H)⁺.

Compound 6741-{4-[4-Isopropylamino-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-cyclopropanol

¹H NMR (METHANOL-d₄) δ 8.61-8.64 (q, J=7.6 Hz, 1H), 8.38 (s, 1H),8.09-8.16 (m, 2H), 7.86-7.88 (d, J=7.6 Hz, 1H), 7.44-7.62 (m, 1H),4.26-4.30 (m, 1H), 1.76-1.23 (m, 8H), 1.10-1.12 (q, J=4 Hz, 2H). LC-MS:m/z 432.2 (M+H)⁺.

Compound 6756-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-N-(2-difluoromethyl-pyridin-4-yl)-N′-isopropyl-[1,3,5]triazine-2,4-diamine

Using the standard procedure described in Example 10 Step 2 exceptreplacing Cs₂CO₃ by t-BuONa yielded 675.

¹H NMR (METHANOL-d₄) δ 8.58-8.46 (m, 2H), 8.18-8.11 (m, 2H), 7.90-7.88(m, 2H), 6.86-6.58 (m, 1H), 4.34-4.32 (m, 1H), 2.17-2.05 (m, 3H), 1.35(d, J=7.2 Hz, 6H). LC-MS: m/z 422.2 (M+H)⁺.

Compound 676N-(2-Fluoromethyl-pyridin-4-yl)-N′-isopropyl-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazine-2,4-diamine

Using the standard procedure described in Example 10 Step 2 exceptreplacing Cs₂CO₃ by t-BuONa yielded 676.

¹H NMR (METHANOL-d₄) δ 8.72-8.70 (m, 1H), 8.40-7.98 (m, 5H), 5.55 (s,1H), 5.43 (s, 1H), 4.52-4.33 (m, 1H), 1.34 (d, J=8.4 Hz, 6H). LC-MS: m/z408.1 (M+H)⁺.

Compound 6772-(4-{4-[6-(1,1-Difluoro-ethyl)-pyridin-2-yl]-6-isopropylamino-[1,3,5]triazin-2-ylamino}-pyridin-2-yl)-2-methyl-propionitrile

¹H NMR (METHANOL-d₄) δ 8.61 (d, J=6.8 Hz, 1H), 8.45 (s, 1H), 8.40 (d,J=5.2 Hz, 1H), 8.11 (t, J=7.6 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.62 (s,1H), 2.12 (t, J=19.2 Hz, 3H), 1.13 (d, J=6.4 Hz, 6H). LC-MS: m/z 439.2(M+H)⁺.

Compound 6782-{4-[4-(2-Hydroxy-2-methyl-propylamino)-6-(6-trifluoromethyl-pyridin-2-yl)-[1,3,5]triazin-2-ylamino]-pyridin-2-yl}-2-methyl-propionitrile

¹H NMR (METHANOL-d₄) δ 8.80-8.78 (m, 1H), 8.45 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 8.22 (t, J=7.8 Hz, 1H), 8.79 (d, J=8.0 Hz, 1H), 7.60 (dd, J=3.6Hz, 2.0 Hz, 1H), 3.63 (d, J=11.6 Hz, 2H), 1.80 (s, 6H), 1.31 (d, J=6.0Hz, 6H). LC-MS: m/z 473.2 (M+H)⁺.

Example 11 Preparation of Compounds of Formula I where Ring A is6-Aminopyridyl

Example 11, Step 1

The preparations of the following intermediates are analogous to theprocedure as Scheme 3, Step 4, using the appropriate starting materialsand intermediates:

Compound 679 Methyl(6-(4-(isopropylamino)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-yl)carbamate

LCMS: m/z 449.3 (M+H)⁺.

Compound 680 Methyl6-(4-(2-hydroxy-2-methyl-propylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-yl-carbamate

LCMS: m/z 479.3 (M+H)⁺.

Compound 681 Methyl6-(4-(neopentylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 477.3 (M+H)⁺.

Compound 682 Methyl6-(4-(3,5-difluorophenylamino)-6-(1-methylcyclopropylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 428.2 (M+H)⁺.

Methyl6-(4-(1-methylcyclopropylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 461.3 (M+H)⁺.

Compound 683 Methyl6-(4-(2-(trifluoromethyl)pyridin-4-ylamino)-6-(1,1,1-trifluoro-propan-2-ylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 503.2 (M+H)⁺.

Compound 684 Methyl6-(4-(3,5-difluorophenylamino)-6-(2-hydroxy-2-methylpropyl-amino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 446.1 (M+H)⁺.

Preparation of methyl6-(4-(tert-butylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

Using the standard procedure described above to give Compound 685-methyl6-(4-(tert-butylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 463.3 (M+H)⁺.

Compound 686 Methyl6-(4-(2-(1,1-difluoroethyl)pyridin-4-ylamino)-6-(isopropyl-amino)-1,3,5-triazin-2-yl)pyridin-2-ylcarbamate

LCMS: m/z 445.1 (M+H)⁺.

Example 11, Step 2 Preparation of6-(6-aminopyridin-2-yl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

To a solution of6-(6-Chloro-pyridin-2-yl)-N-oxetan-3-yl-N′-(2-trifluoromethyl-pyridin-4-yl)-[1,3,5]triazine-2,4-diamine(170 mg, 0.38 mmol) in methanol (6 mL) was added 5 pellets of KOH. Themixture was heated to 80° C. for 12 hours. TLC (ethyl acetate) showedthat the reaction was complete. The mixture was adjusted pH to 7 andfiltered, the filtrate was concentrated and purified by a standardmethod to give6-(6-aminopyridin-2-yl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine.

The following compounds were prepared according to the procedure setforth in Example 11, Step 2, using appropriate starting materials andreagents:

Compound 6876-(6-aminopyridin-2-yl)-N2-isopropyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.5-8.65 (m, 1.5H), 7.8-8.3 (m, 3.5H), 7.2 (m,1H), 4.2-4.6 (m, 1H), 1.25-1.4 (m, 6H). LC-MS: m/z 391.3 (M+H)⁺.

Compound 6896-(6-aminopyridin-2-yl)-N2-neopentyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.75 (m, 1H), 8.1-8.6 (m, 2H), 7.6-7.8 (m, 2H),6.85 (m, 1H), 3.4-3.5 (m, 2H), 1.0 (s, 9H). LC-MS: m/z 419.3 (M+H)⁺.

Compound 6906-(6-aminopyridin-2-yl)-N2-isobutyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

Compound 6911-(4-(6-aminopyridin-2-yl)-6-(3,5-difluorophenylamino)-1,3,5-triazin-2-ylamino)-2-methylpropan-2-ol

1H NMR (METHANOL-d₄): δ 8.6-7.6 (m, 3H), 7.55-6.5 (m, 3H), 3.5-3.7 (m,2H), 1.1-1.4 (m, 6H). LC-MS: m/z 338.2 (M+H)⁺.

Compound 6926-(6-aminopyridin-2-yl)-N2-(1-methylcyclopropyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄): δ 8.88 (m, 1H), 8.5 (m, 1H), 7.85 (m, 1H), 7.7 (m,1H), 7.6 (m, 1H), 6.75 (m, 1H), 1.52 (s, 3H), 0.75-0.95 (m, 4H). LC-MS:m/z 403.2 (M+H)⁺.

Compound 6936-(6-aminopyridin-2-yl)-N2-(3,5-difluorophenyl)-N4-(1-methylcyclopropyl)-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄): δ 7.5-7.58 (m, 4H), 6.5-6.8 (m, 2H), 1.5 (s, 3H),0.75-0.95 (m, 4H). LC-MS: m/z 370.2 (M+H)⁺.

Compound 6946-(6-aminopyridin-2-yl)-N2-(2-(trifluoromethyl)pyridin-4-yl)-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 78.63-7.75 (m, 4H), 7.6 (m, 1H), 6.68 (m, 1H),5.5-5.0 (m, 1H), 1.48 (m, 3H). LC-MS: m/z 445.2 (M+H)⁺.

Compound 6956-(6-aminopyridin-2-yl)-N2-tert-butyl-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.55-8.65 (m, 2H), 7.9-8.25 (m, 2H), 7.8-7.9 (m,1H), 7.2 (m, 1H), 1.55 (m, 9H). LC-MS: m/z 405.2 (M+H)⁺.

Compound 6966-(6-aminopyridin-2-yl)-N2-(2-(1,1-difluoroethyl)pyridin-4-yl)-N4-isopropyl-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 8.55-8.2 (m, 2H), 8.0-7.55 (m, 3H), 6.75 (m,1H), 4.55-4.2 (m, 1H), 2.0 (t, 3H), 1.3 (d, J=6.4 Hz, 3H). LC-MS: m/z387.3 (M+H)⁺.

Compound 697N-(6-(4-(isopropylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-yl)pyridin-2-yl)acetamide

¹H NMR (METHANOL-d₄): δ 8.7-8.5 (m, 2H), 8.3-7.8 (m, 4H), 4.5-4.2 (m,1H), 2.23 (s, 3H), 1.25-1.35 (m, 6H). LC-MS: m/z 433.2 (M+H)⁺.

Compound 6986-(6-aminopyridin-2-yl)-N2-(tert-butyl)-N4-(3,5-difluorophenyl)-1,3,5-triazine-2,4-diamine

1H NMR (METHANOL-d₄): δ 7.68-7.48 (m, 4H), 6.73-6.55 (m, 2H), 1.58 (s,9H). LC-MS: m/z 372.2 (M+H)⁺.

Compound 6996-(6-aminopyridin-2-yl)-N2-(cyclopropylmethyl)-N4-(3,5-difluorophenyl)-1,3,5-triazine-2,4-diamine

¹H NMR (METHANOL-d₄): δ 7.71-7.50 (m, 4H), 6.74-6.72 (m, 1H), 6.56-6.54(m, 1H), 3.43-3.36 (m, 2H), 1.18-1.72 (m, 1H), 0.56-0.54 (m, 2H),0.32-0.31 (m, 2H). LC-MS: m/z 370.1 (M+H)⁺.

Example 12 Enzymatic and Cell Assays

Enzymatic Assay.

Compounds are assayed for IDH2 R172K inhibitory activity through acofactor depletion assay. Compounds are preincubated with enzyme, thenthe reaction is started by the addition of NADPH and α-KG, and allowedto proceed for 60 minutes under conditions previously demonstrated to belinear with respect for time for consumption of both cofactor andsubstrate. The reaction is terminated by the addition of a secondenzyme, diaphorase, and a corresponding substrate, resazurin. Diaphorasereduces resazurin to the highly fluorescent resorufin with theconcomitant oxidation of NADPH to NADP, both halting the IDH2 reactionby depleting the available cofactor pool and facilitating quantitationof the amount of cofactor remaining after a specific time period throughquantitative production of an easily detected fluorophore.

Specifically, into each of 12 wells of a 384-well plate, 1 μl of 100×compound dilution series is placed, followed by the addition of 40 μl ofbuffer (50 mM potassium phosphate (K₂HPO₄), pH 7.5; 150 mM NaCl; 10 mMMgCl₂, 10% glycerol, 0.05% bovine serum albumin, 2 mMbeta-mercaptoethanol) containing 1.25 μg/ml IDH2 R172K. The testcompound is then incubated for one hour at room temperature with theenzyme; before starting the IDH2 reaction with the addition of 10 μl ofsubstrate mix containing 50 μM NADPH and 6.3 mM α-KG in the bufferdescribed above. After a further one hour of incubation at roomtemperature, the reaction is halted and the remaining NADPH measuredthrough conversion of resazurin to resorufin by the addition of 25 μlStop Mix (36 μg/ml diaphorase enzyme and 60 μM resazurin; in buffer).After one minute of incubation the plate is read on a plate reader atEx544/Em590.

For determination of the inhibitory potency of compounds against IDH2R140Q in an assay format similar to the above, a similar procedure isperformed, except that the final testing concentration is 0.25 μg/mlIDH2 R140Q protein, 4 μM NADPH and 1.6 mM α-KG.

For determination of the inhibitory potency of compounds against IDH2R140Q in a high throughput screening format, a similar procedure isperformed, except that 0.25 μg/ml IDH2 R140Q protein was utilized in thepreincubation step, and the reaction is started with the addition of 4μM NADPH and 8 μM α-KG.

U87MG pLVX-IDH2 R140Q-neo Cell Based Assay.

U87MG pLVX-IDH2 R140Q-neo cells are grown in T125 flasks in DMEMcontaining 10% FBS, 1× penicillin/streptomycin and 500 μg/mL G418. Theyare harvested by trypsin and seeded into 96 well white bottom plates ata density of 5000 cell/well in 100 μl/well in DMEM with 10% FBS. Nocells are plated in columns 1 and 12. Cells are incubated overnight at37° C. in 5% CO₂. The next day compounds are made up at 2× concentrationand 100 ul are added to each cell well. The final concentration of DMSOis 0.2% and the DMSO control wells are plated in row G. The plates arethen placed in the incubator for 48 hours. At 48 hours, 100 ul of mediais removed from each well and analyzed by LC-MS for 2-HG concentrations.The cell plate is placed back in the incubator for another 24 hours. At72 hours post compound addition, 10 mL/plate of Promega Cell Titer Gloreagent is thawed and mixed. The cell plate is removed from theincubator and allowed to equilibrate to room temperature. Then 100 ul ofreagent is added to each well of media. The cell plate is then placed onan orbital shaker for 10 minutes and then allowed to sit at roomtemperature for 20 minutes. The plate is then read for luminescence withan integration time of 500 ms to determine compound effects on growthinhibition.

The data for various compounds of one aspect of the invention in theR140Q enzymatic assay, R140Q cell-based assay and R172K enzymatic assayas described above or similar thereto are presented below in Table 2.For each assay, values indicated as “A” represent an IC50 of less than100 nM; values indicated as “B” represent an IC50 of between 100 nM and1 μM; values indicated as “C” represent an IC50 of greater than 1 μM to10 μM; values indicated as “D” represent an IC50 of greater than 10 μM;values indicated as “no fit” are inactives and blank values representthat the compound was either inactive or not tested in that particularassay.

TABLE 2 Enzymatic and Cellular Activity of Compounds. Cmpd Enz Cell EnzNo R140Q R140Q R172K 100 A A A 103 B C C 108 B 109 B C C 110 A A B 111 AA A 112 A B B 113 A A B 114 B C C 115 A B B 116 B C 117 B C 118 A B B119 B C D 120 A A B 121 A A A 122 B C C 123 A B B 126 A A B 128 B C C129 A B C 130 A A B 132 A A B 133 B D 135 B C D 137 B C 139 A B C 140 AB C 141 A B B 143 A B B 145 B C D 146 A A B 147 B B C 148 B B C 149 A AA 150 B B C 151 B B B 154 A B C 155 B No Fit D 156 B B C 158 A B B 159 BB C 160 A B B 162 B C C 165 B C 167 A A B 168 A A B 169 A B B 170 B C B172 A B B 173 A A A 174 A A B 175 A A B 176 A B B 177 A A B 178 A A A179 A A A 181 A A B 182 B 183 A A B 184 A B C 185 A B B 186 A A B 187 AA B 188 A A B 189 A B C 190 A A B 191 A A B 193 A A B 194 A A A 195 A AB 196 A A B 197 A A B 198 A A B 199 A A A 200 A A B 201 A B C 202 A A A203 A B C 204 A B C 205 A A B 206 A B B 207 B 208 A B B 209 A B B 210 AA B 211 A B B 212 A A B 213 A A B 214 A B B 215 A B C 216 A B B 217 A C218 A B C 219 A A B 220 A A B 221 B B C 222 B 223 A A A 224 A B B 225 AB C 226 A B B 227 A A B 228 A B B 229 A A A 230 B B B 231 B 232 A B B233 A A B 234 No Fit 235 B B C 236 B B C 237 B B C 238 B B C 239 A A B240 A B C 241 A B C 242 B B C 243 B C 244 B C B 245 A B B 246 B A B 247A A A 248 A B C 249 A B B 250 A B B 251 B 252 B C 253 A A B 254 A B B255 A A B 256 C 257 A B B 258 C 259 B B D 260 A A A 261 A A B 262 B B C263 A B C 264 C 265 B C 266 A B C 267 A B C 268 A B B 269 A A B 270 A BB 271 No Fit 272 B B 273 D 274 D 275 B B 276 B 277 A B 278 No Fit 279 D280 D 281 A B 282 No Fit 283 No Fit 284 B B 285 C 286 D 287 B 288 A A289 A B 290 B A 291 No Fit No Fit 292 No Fit No Fit 293 A A 294 No FitNo Fit 295 A A 296 B A 297 A A 298 A A 299 A B 300 B B 301 B A 302 A B303 C No Fit 304 C No Fit 305 D No Fit 306 B A 308 A B 309 A A 310 B A311 B B 312 B C 313 A A 314 C No Fit 315 A A 316 B B 317 A A 318 A A 319B A 320 A A 321 A A 322 B A 323 B A 324 B C 325 A A 326 B A 327 B B 328A A 329 A A 330 B A 331 B A 332 D No Fit 334 B A A 335 B A A 336 B A B337 B B C 340 A A A 341 A A B 342 B C C 343 B B 344 B A A 345 B B B 346A B 347 B 348 D 350 B B C 351 A B 352 A A 353 B A 354 B A 355 B A 356 BA 358 B A B 359 B B 360 B B 361 B B 362 B B 363 B A 364 C B 365 C 366 BA 367 B A 368 C A 369 A A 370 A A 371 A A 372 A A A 374 A A A 376 B A377 B A 378 B A 379 B A 380 B B 381 B A 382 B A 383 B A 384 B A 385 C B386 B A A 387 A A 388 C B 389 C A 390 C B 391 B A 392 B A 393 B A 394 AA 395 B A 396 B A 397 B B 398 A A 399 B A 400 B A 401 B A 402 B A 403 BA 404 B A 405 C B 406 B A 407 B B 408 B A 409 B A B 410 D B 411 C A 412C 413 D 414 B B 415 D 416 A A B 450 B A 451 B A 452 B C D 454 B B C 455B A A 456 B A B 458 B A B 459 A A A 460 A A A 461 A A A 462 B B B 463 BA A 464 B A A 465 B A A 466 B A B 467 B B B 468 B A A 469 A A A 470 B AB 471 B A B 472 A A B 473 A A A 474 B A A 475 A A A 476 A A B 477 B A A478 B A A 479 B A B 480 B A B 481 B A A 482 B A A 483 B B C 484 B A B485 B A B 486 B B 491 B A A 492 B A A 493 A A 495 B A A 496 B A A 497 BA B 498 B B C 499 B A A 500 B A A 501 B B C 502 B B C 503 C A A 504 B AA 505 B A B 508 B A B 509 B A B 510 B A A 511 B A B 512 B A B 513 C A B514 B A A 516 B A A 517 B A A 518 B A A 519 B A B 521 B A A 522 B A B523 B A A 524 B A A 526 B A A 527 B A A 528 B A B 529 B A A 530 B A B531 B A A 532 B A A 533 B A A 534 B A A 535 B A B 536 C A B 537 B A A538 C A B 540 B A B 541 B A B 542 B A A 543 B A B 544 B A B 545 B A B546 B A B 547 B A A 548 B A B 549 B A A 550 B A A 551 B A A 552 B A B554 B A B 555 B A C 556 B A A 559 B A A 560 B A A 561 B A A 562 B A A563 B A A 564 B A A 565 B A A 567 B A A 568 B A B 569 B B B 570 B A A571 B A B 572 B A B 574 B A A 576 B A B 577 C A B 581 B A A 582 B A A583 B A A 584 B A A 585 B A A 587 B A A 588 B A B 592 B A B 593 B A A594 B A B 595 B A A 596 B A A 597 B A A 598 B A A 599 B A A 600 B A A601 B A A 602 B A A 603 B A A 604 B A A 605 B A B 606 B A A 607 B A B608 B A A 609 B A A 610 B A A 611 B A B 612 B A A 613 B A A 614 B A A615 B A B 616 B A A 617 B A A 618 B A A 619 B A A 621 B B C 622 B B B623 B B C 624 B A B 625 A A B 626 B B C 627 A A A 628 A A B 629 A A A630 A A A 631 A A A 632 B A B 633 B A A 634 B A A 635 B B B 636 A A B637 B A B 638 B A B 639 B A A 640 A A A 641 B A A 642 B A A 644 B C 645B A B 646 B A A 647 B A B 648 B A B 649 A B B 650 B B C 651 B A B 652 BB B 653 B A B 654 B A D 655 B B B 657 B A B 658 B A A 660 B C 662 B C663 A A 665 A A 667 B B B 669 B A A 670 B A B 671 B A A 672 B A B 673 BA A 674 B A B 675 B A A 676 B A A 677 B A A 678 C A B 679 B B D 687 B AA 689 B A A 690 B A A 691 B A B 692 B A A 693 B A A 694 B A A 695 B A A696 B A B 697 B B C 698 B A A 699 B A A

In some embodiments, one aspect of the invention provides a compoundselected from any one of Compounds Nos 100, 110, 111, 112, 113, 115,118, 120, 121, 123, 126, 129, 130, 132, 139, 140, 141, 143, 146, 149,154, 158, 160, 167, 168, 169, 172, 173, 174, 175, 176, 177, 178, 179,181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 193, 194, 195, 196,197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 208, 209, 210, 211,212, 213, 214, 215, 216, 217, 218, 219, 220, 223, 224, 225, 226, 227,228, 229, 232, 233, 239, 240, 241, 245, 246, 247, 248, 249, 250, 253,254, 255, 257, 260, 261, 263, 266, 267, 268, 269, 270, 277, 281, 288,289, 290, 293, 295, 296, 297, 298, 299, 301, 302, 306, 308, 309, 310,313, 315, 317, 318, 319, 320, 321, 322, 323, 325, 326, 328, 329, 330,331, 334, 335, 336, 340, 341, 344, 346, 351, 352, 353, 354, 355, 356,358, 363, 366, 367, 369, 370, 371, 372, 374, 376, 377, 378, 379, 381,382, 383, 384, 386, 387, 391, 392, 393, 394, 395, 396, 398, 399, 400,401, 402, 403, 404, 406, 408, 409, 416, 450, 455, 456, 458, 459, 460,461, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476,477, 478, 479, 480, 481, 482, 484, 485, 491, 492, 493, 495, 496, 497,499, 500, 504, 505, 508, 509, 510, 511, 512, 514, 516, 517, 518, 519,521, 522, 523, 524, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535,537, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552,554, 555, 556, 559, 560, 561, 562, 563, 564, 565, 567, 568, 570, 571,572, 574, 576, 581, 582, 583, 584, 585, 587, 588, 592, 593, 594, 595,596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609,610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 624, 625, 627, 628,629, 630, 631, 632, 633, 634, 636, 637, 638, 639, 640, 641, 642, 645,646, 647, 648, 649, 651, 653, 654, 657, 658, 663, 665, 669, 670, 671,672, 673, 674, 675, 676, 677, 687, 689, 690, 691, 692, 693, 694, 695,696, 698 and 699. In a more specific aspect of this embodiment, theinvention provides a compound selected from any one of Compound Nos.100, 110, 111, 113, 120, 121, 126, 130, 132, 146, 149, 167, 168, 173,174, 175, 177, 178, 179, 181, 183, 186, 187, 188, 190, 191, 193, 194,195, 196, 197, 198, 199, 200, 202, 205, 210, 212, 213, 219, 220, 223,227, 229, 233, 239, 246, 247, 253, 255, 260, 261, 269, 288, 290, 293,295, 297, 298, 301, 306, 309, 310, 313, 315, 317, 318, 319, 320, 321,323, 325, 326, 328, 329, 330, 331, 336, 340, 341, 352, 353, 354, 355,356, 358, 363, 366, 367, 369, 370, 371, 372, 374, 376, 377, 378, 379,381, 382, 383, 384, 387, 391, 392, 393, 394, 395, 396, 398, 399, 400,401, 402, 403, 404, 406, 408, 409, 416, 450, 451, 456, 458, 459, 460,461, 466, 469, 470, 471, 472, 473, 475, 476, 479, 480, 484, 485, 493,497, 505, 508, 509, 511, 512, 519, 522, 528, 530, 535, 540, 541, 543,544, 545, 546, 548, 552, 554, 555, 568, 571, 572, 576, 588, 592, 594,605, 607, 611, 615, 624, 625, 627, 628, 629, 630, 631, 632, 636, 637,638, 640, 645, 647, 648, 651, 653, 654, 657, 663, 665, 670, 672, 674,691 and 696.

In some embodiments, one aspect of the invention provides a compoundselected from any one of Compounds Nos 100, 110, 111, 112, 113, 115,118, 120, 121, 123, 126, 129, 130, 132, 139, 140, 141, 143, 146, 149,154, 158, 160, 167, 168, 169, 172, 173, 174, 175, 176, 177, 178, 179,181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 193, 194, 195, 196,197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 208, 209, 210, 211,212, 213, 214, 215, 216, 217, 218, 219, 220, 223, 224, 225, 226, 227,228, 229, 232, 233, 239, 240, 241, 245, 246, 247, 248, 249, 250, 253,254, 255, 257, 260, 261, 263, 266, 267, 268, 269, 270, 277, 281, 288,289, 290, 293, 295, 296, 297, 298, 299, 301, 302, 306, 308, 309, 310,313, 315, 317, 318, 319, 320, 321, 322, 323, 325, 326, 328, 329, 330,331, 334, 335, 336, 340, 341, 344, 346, 351, 352, 353, 354, 355, 356,358, 363, 366, 367, 369, 370, 371, 372, 374, 376, 377, 378, 379, 381,382, 383, 384, 386, 387, 391, 392, 393, 394, 395, 396, 398, 399, 400,401, 402, 403, 404, 406, 408, 409, and 416. In a more specific aspect ofthis embodiment, the invention provides a compound selected from any oneof Compound Nos. 100, 110, 111, 113, 120, 121, 126, 130, 132, 146, 149,167, 168, 173, 174, 175, 177, 178, 179, 181, 183, 186, 187, 188, 190,191, 193, 194, 195, 196, 197, 198, 199, 200, 202, 205, 210, 212, 213,219, 220, 223, 227, 229, 233, 239, 247, 253, 255, 260, 261, 269, 288,293, 295, 297, 298, 309, 313, 315, 317, 318, 320, 321, 325, 328, 329,340, 341, 352, 369, 370, 371, 372, 374, 387, 394, 398, and 416.

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

1-19. (canceled)
 20. A compound which is

or a pharmaceutically acceptable salt or hydrate thereof.
 21. Thecompound of claim 20, wherein the compound is


22. A pharmaceutical composition comprising a compound of claim 20, anda pharmaceutically acceptable carrier.
 23. A method of treating a cancercharacterized by the presence of an IDH2 mutation, wherein the IDH2mutation results in a new ability of the enzyme to catalyze the NAPHdependent reduction of a ketoglutarate to R(−) 2 hydroxyglutarate in apatient, comprising the step of administering to the patient in needthereof a compound of claim
 20. 24. The method of claim 23, wherein theIDH2 mutation is an IDH2 R140Q or R172K mutation.
 25. The method ofclaim 23, wherein the IDH2 mutation is an IDH2 R140Q mutation.
 26. Themethod of claim 23, wherein the cancer is selected from glioblastoma,myelodysplastic syndrome, myeloproliferative neoplasm, acute myelogenousleukemia, sarcoma, melanoma, non small cell lung cancer, chondrosarcoma,cholangiocarcinomas or angioimmunoblastic non-Hodgkin's lymphoma. 27.The method of claim 23, wherein the cancer is acute myelogenousleukemia.
 28. The method of claim 23, further comprising administeringto the patient in need thereof a second therapeutic agent useful in thetreatment of cancer.